D-ring substituted 6-deoxytetracyclines

ABSTRACT

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAE   1-(R4-N(-R3)-),2,4,5,6-TETRA(O=),3-X4,4A-(HO-),7-X2,9-X,   10-X1,11-A-1,2,3,4,5,6,11,12-OCTAHYDRONAPHTHACENE   AND   1-(R4-N(-R3)-),2,4,5,6-TETRA(O=),3-X4,7-X2,9-X,10-X1,11-A-   1,2,3,4,5,6,11,12-OCTAHYDRONAPHTHACENE   WHEREIN X IS SELECTED FROM THE GROUP CONSISTING OF AMINO, MONOLOWER ALKYLAMINO, ALKANOYLAMINO HAVING 2 TO 4 CARBON ATOMS, LOWER ALKYL AND LOWER ALKOXY; X1 IS SELECTED FROM THE GROUP CONSISTING HYDROGEN AND CHLORO; X2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROXY AND LOWER ALKOXY; A IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL; R3 AND R4 WHEN TAKEN TOGETHER WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED FORM A NITROGEN HETEROCYCLIC RING SELECTED FROM THE GROUP CONSISTING OF PIPERAZINO, PIPERIDINO, MORPHOLINO, PYRROLO, THIOMORPHOLINO, PYRROLIDINO AND 2-(LOWER CARBALKOXY)PYRROLIDINO; R3 AND R4 WHEN TAKEN SEPARATELY ARE EACH SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKANOYL HAVING 1 TO 4 CARBON ATOMS, AND CH2B1 WHEREIN B1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL AND MONO-SUBSTITUTED LOWER ALKYL, SAID SUBSTITUENT BEING SELECTED FROM THE GROUP CONSISTING OF HYDROXY AND LOWER ; PROVIDED THAT ONLY ONE OF SAID R3 AND R4 SUBSTITUENTS IS SELECTED FROM THE GROUP CONSISTING OF ALKANOYL HAVING 1 TO 4 CARBON ATOMS; X4 IS SELECTED FROM THE GROUP CONSISTING OF CYANO AND -CO-NH-R6 WHEREIN R6 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKYL.

United States Patent D-RING SUBSTITUTED 6-DEOXYTETRACYCLINES Lloyd H.Conover, Barham, near Canterbury, England, andRobert B. Woodward,Belmont, Mass., assignors to Pfizer Inc., New York, N.Y.

No Drawing. Application Oct. 31, 1969, Ser. No. 873,077,

now Patent No. 3,697,552, which is a division of application Ser. No.569,052, Aug. 1, 1966, now Patent No. 3,509,184, which is acontinuation-impart of application Ser. No. 209,269, July 11, 1962,which in turn is a continuation-in-part of application Ser. No. 132,304,Aug. 18, 1961, both now abandoned. Divided and this application Mar. 7,1972, Ser. No. 232,609

Int. Cl. C07c 103/19 U.S. Cl. 260-559 AT 6 Claims ABSTRACT OF THEDISCLOSURE The total synthesis of tetracycline-type antibiotics by amultistep process beginning with 3,4,10-trioxo-1,2,3,4,4a,9,9a,l0-octahydroanthracenes comprising: (1) an aldol condensation witha glyoxalic acid ester to give a 2-carboxymethylidene-3 ,4,IO-trioxol,2,3,4,4a,9,9a, 10 octahydroanthracene ester; (2) Michaelreaction of said ester with an amine to produce a3,4,10-trioxo-1,2,3,4,4a,9, 9a,IO-OCtahydrQanthracene-Z-(a-amino)aceticacid ester; (3) conversion of the triketone to the corresponding 4,10-diketone by (a) selective reduction of the Michael reaction product tothe corresponding 3-hydroxy compound, followed by conversion of the3-hydroxy compound to the corresponding 3-formyloxy compound and removalof the 3-formyloxy group by treatment with zinc dust to give a4,10-dioxo-1,2,3,4,4a,9,9a,lfl-octahydroanthracene-Z (atamino) aceticacid est er; or (b) conversion of the hydrochloride salt of the Michaelreaction product to a lactone by reaction with p-toluene-sulfonic acidand treatment of the lactone with zinc dust formic acid; (4) conversionof the 4, l0-diketo-l,2,3,4,4a,9',9a, l O-octahydroanthracene-Z-(a-amino)acetic acid to a mixed anhydride; (5) followed by acylation ofa malonic acid ester with the mixed anhydride; (6) cyclization of theacyl malonate derivative to a 12a-deoxytetracycline which is thenhydroxylated to a tetracycline. The preparation of the3,4,10-trioxo-1,2,3, 4,4a,9,9a,l0 octahydroanthracenes from benzoylhalides by (a) Friedel-Crafts reaction of a benzoyl halide with apyrocatechol ether, e.g., a di-(l0wer)alkyl ether, to produce a3,4-di-(lower)alkoxybenzophenone; (b conversion of the benzophenone bypartial or complete reduction of the carbonyl group by chemical orcatalytic methods to a 3,4-di-(lower)alkoxy diphenyl methanol or 3,4-di-(lower) alkoxy diphenyl methane; or to a 3,4-di-(l0wer) alkoxy diphenylalkane via a Grignard reaction and reduction of the thus-producedalkanol; (c) oxidation of the 3,4-di-(lower)alkoxy diphenyl alkane. orthe corresponding dihydroxy compound, to a dienedioic acid ester ordienedioic acid; (d) hydrogenation of athe dienedioic acid compound to abenzyl adipic acid derivative; (e) cyclization of said compound to a2-(2-carbalkoxyethyl)-4-tetraloneby means of dehydrating ordehydrohalogenating agents; (f) cyclization of the 4-tetralonederivatives by condensation with a dialkyloxalate to give a 2-carbalkoxy3,4,10-trioxo-octahydroanthracene; and (g) removal of the 2-substituentby decarboxylation. The intermediates and final products are useful asbactericides and/ or chelating agents.

CROSS-REFERENCES TO RELATED APPLICATIONS The application is a divisionof application Ser. No. 873,077 filed Oct. 31, 1969, and now U.S. Pat.3,697,552 which in turn is a division of application Ser. No. 569,052,

3,849,493 Patented Nov. 19, 1974 filed Aug. 1, 1966 and now U.S. Pat.3,509,184, which in turn is a continuation-in-part of'application Ser.No. 209',- 269, filed July 11, 1962 and now abandoned, which in turn isa continuation-in-part of application Ser. No. 132,- 304, filed Aug. 18,1961 and now abandoned.

BACKGROUND .OF THE INVENTION This invention relates to a process ofpreparation of antibacterial agents. More particularly, it is concernedwith the discovery of new and novel synthetic routes for the preparationof known as Well as new tetracycline products. It is also concerned withthe new and useful tetracycline products obtained thereby, as well aswith the new intermediates of the process.

The tetracycline antibiotics comprise a group oflbiologically activehydronaphthacene derivatives having thefollowing essential structuralfeatures. The numbering system indicated is that employed by ChemicalAbstracts.

OH O OH 0 Among the biologically active memebrs of this group are thosecontaining the following substituent groups:

Substituents Common N ame 4-N(CH3)2, 6-0H, 6-011 12a-OH Tetracycline.

4-I1 I2(COE3I)z, 5-013, 6-011, 6-CH3, 5-oxytetraeycline.

4- .;I2(O(1)1 2, 6-011, 6-0113, 7-O1, 7-chlorotetracycline.

5-OH, 6'GH33 IZa-OH, 6-OH 4-desdimethylamino-5-oxy-,

tetracycline.

4-N(CH3)1, tS-OHn l2a-OH; fi-deoxytetraeylcine.

4-N(CH )z, 12a-OH 6-de0xy-6-demethyltetra eye ne.

4-N(CHa)z, 6-011, 6-0113, 7-Br, 7-bromotetracycline.

4-N(CH )2, 6-OH, 7-Cl, 12a-OH fi-denfiethylq-chlorotetraeye ne.

G-OH, 6-CH5, IZa-OH 4-desdimethylaminotetracycline.

6-011, 6-CH3, 7-Cl, l2a-OH 4-desdimethylamino-7- chlorotetracycline.

4-N (0113);, 6-OH, 12a-0H G-demethyltetracycline.

12a-OH fi-deoxyo-demethyl--desdimethylaminotetracycline.

The present new processes utilize 3,4,l0-trioxo-1,2",3,4,4a,9,9a,IO-octahydroanthracenes (formula/I) as starting materials toproduce both known and new tetracylines having the formulae.

NRaR4 NRsR4 A H xvn wherein the various terms are as defined below, bythe reaction sequence illustrated in Flow Sheet I. It will beappreciated by those skilled in the art that several alternative routesexist for the conversion of compounds of formula I to the final productsof formulae XVI and XVII. The particular route adopted for thepreparation of a given tetracycline is largely dependent upon economicfactors, such as availability of materials, and yields of reactionproducts throughout the sequence.

Further, the conditions for any reaction in the sequence can, unlessotherwise indicated, be varied within the skill of the art. The actualconditions employed are determined by the above listed factors as wellas by type and availability of equipment.

FLOW SHEET I In the compounds of this sequence, X is selected from thegroup consisting of hydrogen, hydroxy, trifiuoromethyl, amino, mono anddi-lower alkylamino, alkanoylamino containing 2 to 4 carbon atoms, loweralkyl, alkanoyloxy containing 2 to 4 carbon atoms; and OR wherein R isselected from the group consisting of lower alkyl and benzyl;

X is selected from the group consisting of hydrogen, chloro, lower alkyland trifiuoromethyl;

X is selected from the group consisting of hydrogen, hydroxy, and OR inwhich R is as previously defined;

A is selected from the group consisting of hydrogen, lower alkyl, and BOCH(B wherein B is lower alkyl and B is selected from the groupconsisting of hydrogen and lower alkyl;

X is selected from the group consisting of hydrogen, lower alkyl andbenzyl;

R is selected from the group consisting of X and CO X (mixed anhydride)in which X is lower alkyl;

R and R when taken together with the nitrogen atom to which they areattached from a nitrogen heterocyclic ring selected from the groupconsisting of piperazyl, piperidyl, morpholinyl, pyrryl, pyrrolidyl,2-(lower carbalkoxy)pyrrolidyl, and thiomorpholinyl;

R and R when taken separately are each selected from the groupconsisting of hydrogen, alkanoyl containing 1 to 4 carbon atoms, and CHB wherein B is selected from the group consisting of hydrogen, loweralkyl, and monosubstituted lower alkyl, said substituent being selectedfrom the group consisting of hydroxy and lower alkoxy;

Provided that only one of said R and R substituents is selected from thegroup consisting of alkenoyl containing l to 4 carbon atoms,

X is selected from the group consisting of cyano and II C-NHRs whereinX; is selected from the group consisting of hydrogen iand lower alkyl;

X is selected from the group consisting of Y is selected from the groupconsisting of cyano and lower carbalkoxy.

It should be noted that although the X, X and X terms in the benzenoidmoiety of the above generic structures appear in the same sequence, theyneed not be present in this sequence in actual practice. Thisrepresentation is for convenience only and is not to be taken toindicate, for example, that X always represents the S-substituent, orthat X represents the 6- or the 7-substituent. They can occur in anysequence in the benzenoid moiety.

It should be noted that the various substituents in the finaltetracyclines of formulae XVI and XVII or in the intermediates for theirproduction may be replaced by other groups according to proceduresdescribed hereinafter. Thus, X, X and X may be transformed to hydroxy,hydroxyalkyl, nitro, cyano, carbalkoxy, alkyl sulfonyl, halo sulfonyl,alkyl sulfinyl, and sulfamyl. The A substituent may be transformed to=CHB amino, monoor di-lower alkylamino and CH(B )OH wherein B isselected from the group consisting of hydrogen and alkyl, by appropriatereactions as is discussed below.

A wide variety of 4-aminotetracyclines are, of course, preparedaccording to the present processes by substituting various primary orsecondary alkyl, aralkyl or aryl amines for dimethylamine. Suitableamines include other dialkylamines, e.g. methyl, ethyl, propyl, etc.amines; aralkyl and alkaryl amines, and N-alkyl derivatives thereof,e.g. N-methylaniline, benzylarnine, heterocyclic amines, e.g.pyrrolidine, morpholine; aminopyridines and N-alkyl derivatives thereof;arylamines, e.g. aniline and substituted derivatives thereof wherein thesubstituent is hydroxy, carbalkoxy, nitro and amino; and ammonia.Further, hydroxyalkyl substituents on the nitrogen, where protected forsome of the reaction steps by ether formation or acylation, as discussedbelow, may subsequently be regenerated, e.g., by HBr cleavage orhydrolysis.

Of the present new compounds of particular value arethose containing thefollowing benzenoid moiety:

in which X, X and OR are as described above since these compounds aresuitable for the preparation of known and biologically activetetracycline compounds, i.e. where OR 5. is ,OH and, in addition, newand useful tetracycline com: pounds not previously described.

From XVa to XVb is a selective reduction with ,a suitalicacidderivative, generally a lower alkyl ester. The reaction is.catalyzed by acids or bases, e.g. preferably metal alkoxides. It ispreferably conducted in an inert atmosphere, e.g. nitrogen, at atemperature of from about 80l20 C. for from A to about 24 hours usingfrom about /a to,2.0 molesv metal ion/mole of triketone. The acidcatalyzed condensation is conveniently carried out in glacial acetic,acid as solvent. Non-,hydroxylic solvents such as benzene, xylene,toluene, dioxane, dimethoxyethane, diethyleneglycoldimethylether anddimethylformamide are useful solvents for the metal catalyzedcondensation, especially when using metal alkoxides. Magnesium methoxideis especially useful in this condensation. Of course, when activehydrogen (in addition to that of the fl-diketone' system) is present,one extra equivalent of alkoxide is used per active hydrogen. Thetat-hydroxy ester, wherein the elements of water are added to theunsaturated ester, is also obtained in small yield. Its production isfavored by short reaction periods and low temperatures. Dehydratingagents, such as phosphorous oxychloride in pyridine at C. andp-toluenesulfonic acid in benzene permit dehydration and generation ofthe unsaturation.

The conversion of XVa to XV is a Michael reaction with an amine HNR RThe reaction is conducted at a temperature of from about 70 C. to aboutC. preferably at about 20 C. An excess of the amine is employed; asufiiciently large excess frequently being used to serve both as solventand as reactant. A variety of other solvents can be used and areactually necessary when-the amine is a solid at the temperature of thereaction. Such solvents include tetrahydrofuran, ethylene glycol ethers,diethyleneglycol ethers and chloroform. The only criteria essential forthe solvent are adequate solubility for the reactants, inertnessand asufficiently low freezing point.

The reaction is run for periods of from minutes to 24 hours dependingupon the reactants and temperature employed. Oxygen should be excludedduring the period when the product is in contact with the excess amine.The order of addition of the reactants appears, in general, to beimmaterial to the outcome of the reaction.

In some instances the ester group is transformed to the amidecorresponding to the amine reactant. Primary lower alkylamines may alsoenter into further reaction involving the 3-keto group. This appears tobe a transient or intermediate step in the reaction and, as long as theamine addition product is retained in solution, can be directly reducedto the 3-hydroxy amino acid ester (XVb). Isolation of the amine additionproduct, however, produces what is believed to be a fused lactampossibly via formation of a hydroxy amine at the 3-position followed byelimination of alcohol between the ester and amine groups.

From XV to XVb is, a selective reduction with a suitable chemicalreducing agent, such as metal hydrides, especially sodium borohydride.The reaction is carried out by dissolving the amino acid ester reactantin a suitable reaction-inert solvent such as 1,2-dimethoxyethane,ethylene-glycol ethers, diethyleneglycol ethers and liquid amines. Whenhydroxylic solvents are. employed, e.g. alcohols, an excess of sodiumborohydride is used. Reaction periods of from about 10 minutes to about3 hours are required. Of course, when active hydrogen is present in thereactants, one equivalent of sodium borohydride is required per activehydrogen in addition to that of the fi-diketone system.

Alternatively, the reduction is conducted by adding the sodiumborohydride all at once to a vigorously stirred solution of the aminoacid ester (XV) in one of the aforementioned solvents at 7.0 C. followedby gradual increase in the temperature to 0 C. In this process, asabove, 0.5 to 4.0 moles of reducing agent per mole of 6. amino acidester is. used. A ratio of 1 is, however, preferred (except in caseswhere active hydrogen is present).

From XVa to XVb is a selective reduction with a suitable chemicalreducing agent, such as sodium borohydride, of the Mannich reactionproduct XV. It is represented as a one-step conversion since the Michaelreaction product need not be separated prior to reduction. Simultaneousformation of the corresponding lactone also occurs.

The lactone, of course, serves as a suitable reactant for the productionof XVb by cleavage of ,thelactone ring under mild conditions.

The formation of XIX from XVIII (R =H) is accomplished by formation of amixed anhydride (R =C'O X with a haloalkyl carbonate as described in theJ. Am. Chem. Soc. 75, 6369 (1953) and the J. Org. Chem. 22, 248 (1957).Acylation of a malonic acid ester derivative, e.g., malonic diester,cyanoacetic ester, malonic ester half amide, including N-alkylatedamides and especially the magnesium salt of ethyl t-butyl-malonamateetc., with the mixed anhydride produces the corresponding malonic acidderivative. Reaction is conducted in a suitable solvent system such aschloroform, toluene, benzene, diethylether, acetonitrile,dimethylformamide, nitromethane, dioxane, tetrahydrofuran, ethers ofethyleneglycol and diethyleneglycol at from about 5 to about 35 C. forperiods ranging from 25 minutes to up to 3 days. When R is.

CO X the malonic acid derivative is employed as a magnesium enolateaccording to the procedure of Tarbell and Price (J. Org. Chem, Loc.cit.).

Where X is CONH-alkyl, e.g. t-butyl or isopropyl, carboxamido, treatmentwith concentrated sulfuric acid yields the corresponding unsubstitutedcarboxamide.

The conversion of XIX to XVII is accomplished by standard base-catalyzedacylation using, for example,

sodium alkoxides, sodamide or preferably sodium hydride.

A ratio of at least 4 equivalents of base and desirably a great excessof up to 10 equivalents is employed. A variety of reaction-inertsolvents can be used, e.g. benzene, xylene, toluene, anisole,dimethylformamide. Dimethylformarnide containing a small amount ofmethanol is the preferred solvent. Reaction is conducted under nitrogenat a temperature of from about to about 150 C. preferably C., forperiods of from about 3 minutes to up to 24 hours depending upon thereactants. A period of 5-7 minutes is adequate, indeed preferred, inmost instances. When Y =CN, the 12-imido group which results inhydrolyzed with aqueous acid to the 12-keto group.

The compounds of structure XVI and XVII in which X, is-a carboxamidegroup are biologically active tetracycline products, the latter being12a-deoxytetracyclines which are converted to tetracycline-compounds XVIby introduction of a 12a-hydroxy group by known procedures such asdescribed in the J. Am. Chem. Soc., 81, 4748 (1959).

A preferred method of l2a-hydroxylation is the method described in US.Pat. 3,188,348, issued June 8, 1965, wherein is described thehydroxylation of certain metal chelates of the 12a-deoxytetracyclines.The advantage of this latter process lies in the fact that the hydroxygroup is introduced. cisto the hydrogen at position 4a.

Compounds of structure XVI and XVII in which X is a cyano group areconverted to corresponding carboxamido substituted compounds by themethod described in US. Pat. 3,029,284, issued Apr. 10, 1962 wherein isdescribed the conversion of tetracycline nitriles to the, correspondingcarboxamide by the Ritter Reaction followed by dealkylation of theresulting N-alkylated carboxamide with concentrated mineral acid andwater.

The diketo compound XVIII is obtained from the hydrochloride of XVb viathe lactone by treatment with from about 0.5 to about 2 equivalents ofp-toluenesulfonic acid in a suitable reaction-inert solvent (benzene,toluene, xylene) for periods of from about 5 hours to about 2 days. Atemperature of from about 80-140 C. is satisw factory. The lactonehydrochloride of XVb is then treated with zinc dust-formic acid for abrief period to give XVIII wherein R is hydrogen. A ratio of from 1 to20 equivalents of zinc dust is effective in cleaving the lactone to thefree acid, 67 equivalents are preferred. Formic acid is the solvent ofchoice. However, mixtures of formic acidmethanol-water or of aceticacid-methanol-water, in approximately 1:1:1 ratio, can also be used. Atemperature of about 25 C. is generally used, although this is not acritical level. To avoid reduction of the 4,10-diketo system, it isimportant that mild reaction conditions and brief contact times beemployed. Contact times of from about 30 seconds to several hoursdepending upon the reactants, are operative. In general, however,periods of from 45 seconds to 120 seconds are favored.

Alternatively, conversion of XVb to the diketo compound XVIII (X =CH isaccomplished by reaction with acetoformic anhydride according to knownprocedures followed by removal of the 3-formyloxy group X5=CH o-on byone of the following; treatment with zinc dust-formic acid or zinc dustin aqueous ammonium hydroxide, calcium in liquid ammonia, or catalytichydrogenation (5% Pd-C) in tetrahydrofuran or formic acid. Care must betaken to avoid over-reduction, that is, reduction of the 4,10-ketogroup. For this reason mild conditions are required. When using zincdust-formic acid, for example, reaction is effected at room temperaturewith contact times of brief duration.

The 8-chloro atom of the diketo octahydroanthracene amino acid (XVIII X=CH and R =lI), corresponding to the 7-chloro atom of the finaltetracycline products can, if desired, be readily removed by catalytichydrogenolysis. Pd-C or Pt-C containing 5-10% of the metal are mosteffective for this purpose. Pd-C (10%) is preferred. From about 0.1 to 1weight equivalent is used. Dimethylformamide, tetrahydrofuran, water,ethanol and ethylacetate, preferably ethanol, serve as solvents.Pressures of from about 1 atmosphere to high pressures, e.g. 70atmospheres or higher, and temperatures of from -20 C. to 60 C. orhigher can be used. The preferred conditions are atmospheric pressureand room temperature for periods of about 3 hours. A base is required totake up the hydrogen chloride produced. While a variety of bases, bothorganic and inorganic by nature, can be used, it is preferred to usetriethylamine, generally about 4 equivalents.

When the substituents of the present compounds are hydroxy or amino, theuse of a blocking group is some times advantageous in obtaining highyields during their preparation. Especially useful blocking groups areacyl, benzyl, tetrahydropyranyl, methoxymethyl, methyl and ethylradicals. Benzyl ethers are particularly easily reduced to hydroxylgroups. Tetrahydropyranyl ethers are easily removed under mildly acidicconditions. Acyl groups which may be used include the acetyl, propionyland butyryl, as well as the benzoyl, succinyl, phthaloyl, and the like.The lower alkyl blocking groups are preferred since these compounds arereadily prepared.

When desired the above mentioned blocking groups, i.e., enol etherradicals, may be removed. The enol radicals are hydrolyzed by treatmentwith aqueous acid as is well known by those skilled in the art. When theether radical is benzyl, hydrogenolysis over noble metal catalyst mayalso be used.

In compounds of formula XVII, for example, the compound wherein X, X andA are hydrogen; X is 10- methoxy; R and R are methyl and X isN-t-butylcarboxamido, the IO-methyl ether and the t-butyl group at the2-position are conveniently removed in a single step by treatment with48% HBr for up to minutes at about 100 C. If shorter periods of time,e.g. 5 minutes, are used only the 10 methyl ether may be cleaved.Alternatively, the protective methyl and t-butyl groups can be removedin stepwise fashion. Treatment with 85% H for 2 hours at about roomtemperature removes only the t-butyl group to give the 10-methyl etherof G-demethyl- 6,lla-dideoxytetracycline. The 10 methyl group is thenremoved by treatment with 48% HBr, or with hot concentrated HCl, or hot50% H 50 The new compounds described herein are useful as chelating,complexing or sequestering agents. The complexes formed with polyvalentmetal ions are particularly stable and usually quite soluble in variousorganic solvents. These properties, of course, render them useful for avariety of purposes wherein metal ion contamination presents a problem;e.g. stabilizers in various organic systems, such as saturated andunsaturated lubricating oils and hydrocarbons, fatty acids and Waxes,wherein transition metal ion contamination accelerates oxidativedeterioration and color formation, biological experimentation, metalextraction. They are further useful in analysis of polyvalent metal ionswhich may be complexed or extracted by these materials and as metalcarriers. Other uses common to sequestering agents are also apparent forthese compounds.

In addition, the compounds of Flow Sheet I are especially valuable asintermediates in chemical synthesis particularly in the synthesis of6-deoxytetracycline, 6- deoxy-6-demethyltetracycline and other novelantimicrobial agents bearing structural similarities to the tetracyclineantibiotics. Many of the herein described compounds, especially thosecontaining one or more hydroxy groups in the benzenoid moiety, areuseful as antibacterial agents in their own right.

In the present new process, particularly as applied to the synthesis ofbiologically active tetracyclines, it is preferred to employintermediates in which the hydrogen atoms at the 9a and 2-positions ofthe anthracene ring (corresponding to the 4a and S-positions of thetetracycline nucleus) are in the cis arrangement. For example, preferredcompounds are depicted by the following formula (syn. compounds):

X m X2 1 X2 II ll In general, syn and anti compounds are separable byvirtue of differences in physical properties, e.g. differences insolubility in various solvents. Usually, fractional crystallizationpermits ready separation.

It is a particular advantage of the novel triketo octahydroanthracenesof the present invention that, by virtue of the activating influence ofthe carbonyl oxygen, they equilibrate to the predominately cisconfiguration in the course of preparation. This enables the synthesisto proceed in stereo-specific fashion without the loss of material thatwould otherwise be entailed in the separation of syn and anti compounds.

However, since in the production of compounds of this type, the productmay consist of a mixture comprised of compounds differing in position ofthe anthracene nucleus, i.e. the hydrogen being both cis and trans tothe hydrogen at position 9a, the mixture can be converted to the thepredominately cis arrangement by equilibration in aqueous alkali, e.g.by treatment with aqueoussodium hydroxide or under the influence of theamine in the Mannich reaction. The procedure merely involves dissolvingthe reaction product in aqueous base and allowing the mixture, to standfor periods of several hours to ensure complete equilibration. In lieuof this procedure, equilibration is attained via the Michael reactionusing extended reaction periods.

It is recognized by those in the art that, when such compounds have anasymmetric center in the substituent G, they exist as diastereoisomerswhich, as previously mentioned, may be separated by fractionalcrystallization for each of the syn and anti compounds. Of course, as isknown, diastereoisomers are racemic modifications consisting of twostructures which are mirror images (optical antipodes). The racemicmodifications may be resolved according to standard procedures. In thepresent process it is preferred, however, to utilize thediastereoisomers of the syn compounds since changes in configuration mayoccur during the various procedural steps of the total synthesis totetracycline compounds, thus necessitating costly and time-consumingresolution procedures. The syn diastereoisorners are converted totetracycline products which consist of the normal tetracyclines andtheir 4-epimers which are separable by known procedures. Of course, the4-epitetracyclines are useful in that they are converted to. normaltetracyclines by known procedures.

The starting compounds of structure I are prepared according to thefollowing procedure:

/\/COR5 X l /\/COR5 X1 Xlg/W X2 COR5 X2 11 III l{Ahere R==OH lwhere R2=OR! A I o X A ooin X coin l m X1 l T 2 a, ll 2 ll ll In the aboveformulae, X, X X and A are as previously described with the exceptionthat substituent X is preferably not a nitro group since this groupdeactivates the ring of compounds of structure II in the ring closurereaction to those of structure III; (R is lower alkyl or benzyl) and Ris hydroxyl, benzyloxy, lower alkoxy or halogen (Cl, F, Br, or I).Alternatively, the corresponding nitriles (e.g. Where COR is replaced byCN) may be used. Further, at least one of the two positions of thebenzenoid ring ortho to the diester side chain must be available for thering closure of structure: II compounds. If desired, halogen, (C1 or Br)may be introduced intocompounds of structure I, II, III and IV in whichat least one of the benzenoid substituentsis hydrogen by directhalogenation with a chlorinating or brominating agent by methodsgenerally employed for halogenation of an aromatic ring. A variety ofsuch agents are known to thosein the art and include phosphoruspentachloride and pentabromide, sulfuryl chloride, N-chloro orbromoalkanoamides, e.g. N-chlorand N-bromoacetamide; N-chloro (or bromo).alkanedioic acid imides, e.g. N-halosuccinimide; N-halophthalimide;chlorine; bromine; N-haloacylanilides, e.g. N-bromoacetanilide,propionanilide and the like; 3-chloro-, 3-bromo, 3,5-dichloro and3,S-dibromo-S,S-dimethylhydantoin; pyridinium perbromide and perchloridehydrohalides, e.g. pyridinium perbromide hydrobromide; and lower alkylhypo: chlorites, e.g. tertiary butylhypochlorite.

Of particular value are compounds of the following formula:

in which X, X R and A are as described above, since these compounds aresuitable for the preparation of biologically active tetracyclinecompounds, i.e. where OR is OH, and homologs and analogs thereof.

These compounds are prepared from the corresponding starting compoundsof structure II represented by structure IID com CORs

IID

through the sequences represented by II- III IV I and II VI IV+I. In thering closure reaction of corresponding structure II compounds, it ispreferred that the benzenoid substituent (X para to substituent OR beother than hydrogen to enable the ring closure reaction to proceed inthe position ortho to substituent OR to afiord corresponding structureIII compounds. If there is no substituent pamto OR a halogen group maybe introduced by direct halogenation by conventional methods ashereinbefore described. The para halogen substituent may be removed, ifdesired, by hydrogenolysis, under the usual conditions, of the tetraloneresulting from the ring closure.

The ring closure of compounds II to III is accomplished by any of thecommonly employed methods for such reactions which generally involve theuse of a dehydrating or dehydrohalogenating cyclization agent. Withcompound of structure II, a preferred method when R is OH or alkoxy,involves treatment of the starting compound with such ring closureagents as hydrogen fluoride or polyphosphoric acid. When R in thestarting compound is hydroxyl, it is usually preferred to use hydrogenfluoride; when R is lower alkoxy, polyphosphoric acid. When R5 ishalogen a Friedel-Crafts catalyst, of course, should be employed, e.g.aluminum chloride. m-Hydroxyor alkoxybenzyl compounds of structure IIhaving, ON in: place of COR lend themselves to the Hoesch synthesis(Berichte, 48, 1122 and 50, 462) wherein treatment with dry hydrogentchloride in the presence of zinc chloride leads to imine formation, andvhydrolysis of the latter provides the tetralone keto group.

The condensation of compounds II or III in which R is CR with oxalicester as well as ring closure of compounds IIIa (after esterification ofthe free acid with R OH) are effected by the general methods for estercon densation reactions of this type. Usually the reaction is carriedout in the presence of a strong base such as alkali metal, alkali metalalkoxides and hydrides, sodamide and the like. If the starting compoundin the oxalate condensation contains free hydroxyl, or amino groups itis preferred to block such groups by alkylation or acylation by knownprocedures. After the reaction is completed, the blocking groups may beremoved, if desired. The resulting product from structure II, i.e. thecorresponding 2-carbalkoxy or carbobenzyloxy compound of structure IV,on hydrolysis and decarboxylation yields compounds of structure I;structure VI compounds are first ring closed, e.g. with polyphosphoricacid and then hydrolyzed and decarboxylated to those of structure I.Cleavage of the ether linkage or other blocking groups by any of thegeneral methods, e.g. treatment with mineral acid such as concentratedhydrobromic or hydriodic acid, or when R is benzyl, hydrogenolysis,gives free hydroxy groups in the benzenoid portion.

The starting compounds of the above described processes, i.e. compoundsof structure II, are prepared by the following sequence of reactions:

VII

A B A H X X X X! I X 0R' OH X2 l X l O R OH VIII IX A H X C (MR1 XiE 1II FLOW SHEET II In the above sequence, R and R are lower alkyl orbenzyl; and B is hydrogen or hydroxy. Further, in this sequence a loweralkyl group can be present in the starting diether at the 4-position ofthe aromatic ring, if desired, to produce 3-benzyl 4 (lower alkyl)substituted adipic acid derivatives (II).

The first of these reactions for the preparation of compounds ofstructure VII is by means of Friedel-Crafts reaction, e.g. AlCl incarbon disulfide. The conversion of compounds of structure VII to thoseof VIII in which A and B are hydrogen is by catalytic reduction, e.g.over copper chromium oxide or noble metal, e.g. palladium, catalyst atfrom atmosphere to superatmospheric pressures of hydrogen gas; where Ais alkyl and B hydroxyl, by reaction with a suitable Grignard reagent,e.g. AMgHalogen; where A is alkyl or hydrogen and B is hydrogen, byreduction, i.e. hydrogenolysis, of corresponding compounds 1.2 in whichB is hydroxyl. From VIII to IX is a standard ether hydrolysis, e.g.concentrated hydrobromic acid.

From IX to X is an ozonolysis reaction giving rise to the dienedioicacid which on hydrogenation over a noble metal catalyst, e.g. palladium,palladium on carbon, platinum, platinum oxide, etc., gives compounds ofstructure II. In the ozonolysis reactions to form compounds of structureX it is not possible to employ as starting compounds those of structureIX in which there are adjacent hydroxyl groups in the benzene ringcontaining X, X and X as substituents, since such structures aresusceptible to the oxidation reaction.

Further, in the ozonolysis reaction compounds of structure IX in whichX, X and X are adjacent ether groups or adjacent ether and hydroxygroups cannot be used since they, too, are susceptible of oxidation. Theozonolysis reaction is applicable to compounds of structure VIII,subject of course to the above limitation, wherein 0R represents anether group. In such cases the ester (X) is obtained. In thehydrogenation reaction, compounds of structure X may be used as the freeacids or corresponding benzyl or lower alkyl esters to providecorresponding products of structure II. Of course, benzyl esters mayundergo hydrogenolysis to the free acid.

In addition, appropriate methods are available for reduction of thebenzoyl keto group to a secondary alcohol. For example, 11a and VII canbe reduced with sodium borohydride, or by hydrogenation with palladiumcatalyst in non-acidic media. By other well-known replacement proceduressuch as the following, the secondary alcohol may be converted to areadily replaceable sulfonic ester group, e.g. the tosylate, mesylate,etc., followed by reaction with an alkali metal cyanide, an amine, amalonic ester, or the like, thus alfording means for introduction of acyano, amino or CH(CO B group in the 6-position of the finaltetracycline. The secondary alcohol can also be dehydrated and theresulting unsaturated compound reduced to the corresponding benzylderivative.

In this sequence of reactions, when X and/or X are halogen, care shouldbe taken to avoid prolonged hydrogenations which may result in theremoval of the halogen atom. The possibility of halogen removal may beminimized by the use of a lower alkanoic acid, e.g. acetic or propionicas solvent for the reaction. Of course, if removed, halogen may bereintroduced if desired by the method hereinbefore described.

In those compounds of structure IX in which there are adjacent hydroxygroups in the benzenoid moiety, such groups must be protected bysuitable blocking groups, e.g. etherified with lower alkyl or benzylgroups. Similarly, free amino groups may be acylated. Of course, theetherifying radical of the hydroxy group may difier from thatrepresented by R. If the etherifying radical is benzyl it maysubsequently be removed by hydrogenolysis. Alternatively, all ethergroups can be removed by hydrogen iodide treatment.

As will be appreciated from the preceding reaction sequence, it is mostconvenient to introduce the benzenoid substituents, X, X and X byemploying the appropriately substituted benzoic acid derivative asstarting material. Many of these benzoic acid derivatives arecommercially available, and others may be readily obtained by thoseskilled in the art.

It will be noted that a number of the later steps of the precedingsequences involve reaction conditions which may affect certain of thesubstituent groups signified by X, X and X For instance, in catalytichydrogenation; e.g. VII- XIII, halo groups are subject tohydrogenolysis. Therefore, where halo groups are desired in the finalproduct, these are best introduced subsequent to the hydrogenation by anappropriate substitution reaction.

In commencing the sequence with a substituted benzoyl succinate, it isessential that an ortho ring position be unsubstituted, sincecyclization to form the center ring of 13' the hydroanthracene' occursat this position. For the preparation of the preferred compounds ofstructure I, which bear an OR substituent in the position, the positionof the benzene ring between the OR group and the keto group in thestarting benzoyl succinate should be unsubstituted, to provide for thesubsequent ring closure. On the other hand, it is preferred to have asubstituent in what corresponds to the 8-position of compound I, sincethis precludes cyclization to that position in competition With thedesired cyclization [II- III]. A CF alkyl, or acylamino groupcan beconveniently carried in this posi tion from the outset. Alternatively,an 8-substituent may be introduced during the reaction sequence, priorto the cyclization. For example, compound II may be halogenated at thisposition, e.g. by treatment with chlorine in the presence of a catalyticamount ofiodine or ferric chloride.

Compounds of structure II are also prepared by the following sequencesof reactions.

FLOW SHEET III The conversion of compounds of formula XI to those of XIIis a Claisen-type condensation of the lower alkyl ester of XI withsuccinic acid diesters to provide formula XII compounds. The conversionof compounds of formula XI to XIII is similarly a Claisen condensationusing acetic acid esters. The conversion of compounds of formula XIII toXII is by alkylation reaction with a monohaloacetic acid ester, and theconversion of XIV to 11a is such an alkylation followed by hydrolysisand decarboxylation. The preparation of compounds of formula XIV fromthose of formula XIII is by standard alkylation procedures preferablyusing H C=CHCO R or corresponding nitriles. This conversion may also beeffected by alkylation with a ,B-halo acid derivative or thecorresponding nitrile. Each of these reactions are effected understandard conditions known to those skilled 14 in the art, eg, in areaction-inert solvent in the presence of a base such as Triton B(henzyltrimethylammonium hydroxide), sodamide, sodium hydride and theirobvious equivalents.

The conversion of compounds of formula XII to those of 11a is by knownstandard reactions, e.g. byreaction of formula XII compounds withcorresponding acrylic acid esters of the formula H C=CHCO R in which Aand R are as previously described under the conditions of the Michaelreaction. It may also be effected by alkylation with B-halo-alkanoicacids of the formula Halogen- CH 'CH CO R or of the correspondingnitriles. Hydrolysis anddecarboxylation of these compounds givesstructure IIa compounds. The conversion of structure IIa compounds tothose of structure II is brought about by reactions as previouslydescribed for preparing structure VIII compounds.

The present invention additionally is adaptable for the preparation ofother tetracycline molecules, as follows.

For compounds in which substituent.X is nitro, the tetralone ofstructure III is nitrated by standard procedures, e.g., such asnitric-acetic anhydride-acetic acid mixtures or nitric acid-sulfuricacid mixtures. Those in which X is halogen, cyano, nitro or other suchgroups are prepared by a Sandmeyer reaction of the correspondingdiazonium salt with suitable salt reagents (Cu Cl Cu Br KI, etc.). Thediazonium salt is obtained by diaz-otization of the amino compound,prepared from compounds of structure II in which X is amino or producedby the reduction of the corresponding nitro com pound by conventionalmeans, e.g., chemical means, such as, active metals (Sn) and mineralacids (HCl) or by catalytic hydrogenation, e.g., nickel catalyst andsuperatmospheric pressure.

The amino group may also be introduced into the benzenoid ring bycoupling of aryldiazonium. salts, e.g., benzene diazonium chloride orthe diazonium salt of paminobenzenesulfonic acid, with compounds ofstructure II or III containing a free hydroxy substituent in the 5-position of the 4-tetralone ring (3-position of the benzene ring)followed by reduction of the resulting phenylazo compound, e.g.,catalytic reduction over noble metalcatalysts. An amino group may alsobe introduced in place of the keto carbonyl oxygen of compounds ofstructure VII and XIV by reduction of the corresponding oxime orhydrazone, by reductive ammonolysis of the keto carbonyl group overnoble metal catalysts or by reduction of the keto group to a secondaryhydroxy group by sodium borohydride followed by conversion to thetosylate and replacement of the tosylate group by an amino group.

A further modification of the present invention provides a means ofintroducing a variety of substituents in positions corresponding to the521, and 6-positions of the tetracycline nucleus. This involvesformation of the sec.- ondary alcohol corresponding to structure IIAcompounds represented by the formula:

OR 11b by partial reduction of the corresponding ketone over palladiumcatalyst at superatmospheric pressure until only one molar equivalent ofhydrogenis takenup. Compounds of structure IIB are also intermediatesfor the preparation of -dimethyltetracyclines.

The benzoyl keto group of compounds of structure IIa may be subjected tothe Wittig reaction as described in Angewandte Chemi 71, 260-273 (1959to produce the alkylidene derivatives IIc.

COzR

2 0 3) X H CO H X2 CO by treatment with the ylid prepared from achloroether of the formula (B )CHClOB (where B is lower alkyl and B ishydrogen or lower alkyl). The necessary chloroethers are obtained bystandard treatment of aldehyde acetals of the formula (B )CH(OB with anacid chloride (J. Ork Chem. 231, 1936).

Treatment of compounds IIa in this fashion with the ylid fromchloromethyl ether, for example, converts the keto group to amethoxy-methylene group which may be reduced to methoxymethyl. Thelatter group may be carried through the subsequent steps hereindescribed to the 6-methoxymethyltetracycline. At this point the elementsof methanol may be split out by standard procedures to obtain the6-methylene-6-deoxy-fi-demethyltetracycline.

The products of the above reaction may, in turn, be hydrogenated withnoble metal catalysts:

Subjecting the reduction products to the further synthetic sequencesillustrated herein yields tetracyclines having a 6-CH(B )OB substituent.Treatment of such tetracyclines with liquid hydrogen fluoride results inthe elimination of a mole of alcohol B OI-I and provides tetracyclineshaving a =CH(B at the 6-position. The latter treatment is, for example,conveniently effected after the introduction of the IZa-hydroxyl group.Alternatively, treatment of such teracycltines having a 6-CH(B )OB groupconverts this group to CH(B )OH with concurrent hydrolysis of any ethergroups in the aromatic D-ring.

The products of the Wittig reaction IIC may also be hydrolyzed toaldehydes and the resulting aldehyde group in turn converted bycatalytic hydrogenation to a hydroxvmethyl group. The latter may becarried through the subsequent reaction of synthetic sequence with itsfree hydroxyl group, or preferably, in the form of a lower alkyl ether.

The described procedures are adaptable to the preparation of a varietyof tetracycline molecules, as follows:

For introduction of aromatic nitro groups, the given compound, e.g.tetralone III, is nitrated by standard procedures, such as treatmentwith nitric acid-acetic anhydride-acetic acid mixtures, ornitric-sulfuric acid mixtures. Those in which X is halogen, cyano, halosulfonyl nitro or other such groups may be prepared by Sandmeyerreaction of the corresponding diazonium salt with suitable salt reagents(Cu Cl Cu Br etc.). The diazonium salt is obtained by diazotization ofthe amino compound, which may in turn be prepared by reduction of thecorresponding nitro compound by conventional means, e.g. chemicalreduction with active metals (Sn) and mineral acids (HCl) or catalytichydrogenation, e.g. with nickel catalyst at superatmospheric pressure.Aromatic cyano groups may be further converted to carboxy or carbalkoxygroups where desired by standard hydrolysis and esterification.

The amino group may also be introduced into the benzenoid ring, e.g. incompounds of structure II having a phenolic hydroxyl group, by couplingwith aryldiazonium salts such as benzene diazonium chloride or thediazonium salt of p-aminobenzenesulfonic acid, followed by reduction ofthe resulting phenylazo compound, e.g. by catalytic hydrogenolysis withnoble metal catalysts.

As has been previously pointed out, normal discretion must be employedin subjecting certain of the substituted intermediates to the hereindescribed reaction steps. In the base condensation reactions, thepresence of a substituent having an active hydrogen (e.g. a hydroxyl, oramino group) will necessitate the use of an additional mole of thesodium hydride or other base. The presence of more than one suchsubstituent per molecule is preferably avoided in these reactions, e.g.by the use of protective ether groups as previously described. The sameconsiderations apply to Grignard reactions and hydride reductions.Hydroxyl groups can be subsequently regenerated from their ethers byconventional hydrolytic procedures such as treatment with hydrogenbromide. Similarly, protective benzyl ether groups can subsequently behydrogenolyzed to obtain hydroxyl groups were desired.

In the reduction of benzoyl adipate IIa or benzophenone VII to thecorresponding benzyl derivatives II and VIII, chemical reduction withamalgamated Zinc and HCl by the well-known Clemmensen procedure may beemployed in place of catalytic hydrogenolysis. Any ester groups whichmay be present in the molecule are concurrently hydrolyzed in theClemmensen procedure, and reesterification will therefore be necessary.

Alternative routes or procedures can be used in place of the Clemmensenreduction. Thus, in the reduction of benzoyl adipate Ila tocorresponding benzyl derivative II, the three-step procedure previouslyreferred to is an appropriate alternative to direct reduction; i.e. (1)conversion of the keto group to hydroxyl, e.g. with sodium borohydrideor by mild reduction at room temperature with palladium on carbon inalcohol or other neutral solvent; (2) conversion of the resultingalcohol to the unsaturated compound by dehydration in anhydrous hydrogenfluoride; and (3) rapid hydrogenation of the resulting double bond, e.g.with palladium at room temperature and moderate hydrogen pressure, untilone mole of hydrogen has been consumed. Another alternative reductionprocedure which is suitable is the Wolf-Kishner reaction (Annalen, 394,90, 1912 and J. Russ. Phys. Chem. Soc. 43, 582, 1911) wherein thebenzoyl derivative is converted to a hydrazone, and the latter is inturn reduced to the corresponding benzyl derivative by heating with abase such as sodium ethoxide.

The present invention provides a means of synthesizing tetracyclinecompounds including 8-substituted and other valuable new tetracyclines,not previously described, which are therapeutically useful by virtue oftheir antimicrobial activity.

Those skilled in the art will appreciate that the following examplesprovide a basis for preparing the listed tetracyclines and thecorresponding 12a-deoxy derivatives thereof.

Of particular significance in accordance with this invention are thosefinal tetracycline products (XVI and XVII) wherein a hydroxy group or agroup readily convertible to a hydroxy group (alkoxy or alkanoyloxy) ispresent at the 8-position. An additional substituent of importance inaccordance with this invention is the trifluoromethyl group when presentat the 7- and/or 8-positions of the final tetracyclines.

Some of the new tetracyclines of the present invention are homologs,isomers or closely related analogs of known tetracyclines. Many of thenew tetracyclines are distinguished from prior art compounds by theirpossession of important and desirable properties, such as extended in 17vitro and in viva antibacterial spectra, activity against organismswhich have inherent or acquired resistance to known antibiotics, rapidabsorption, sustained blood levels, freedom from serum binding,preferential tissue distribution at various parts of the body (e.g.kidney, lung, bladder, skin, etc.) which are sites for infection,sustained stability in a variety of dosage forms, resistance tometabolic destruction, broad solubility, and freedom from objectionableacute and cumulative side-effects. The new tetracyclines are useful intherapy, in agriculture, and in veterinary practice both therapeuticallyand as growth stimulants. In addition, they may be employed asdisinfectants and bacteriostatic agents, in industrial fermentations toprevent contamination by sensitive organisms, and in tissue culture, egfor vaccine production.

The various new tetracyclines of the present invention which do notshare the antibacterial activity of the known tetracyclines are valuableintermediates in the preparation of other compounds of classes known tocontain biologically active members. Thus, the D-ringcan be nitrateddirectly and the nitro derivative reduced catalytically to anaminotetracycline. Further, the tetracycline products of this inventioncan be halogenated by known methods at the 11a-, or in the case of a7-unsubstitutedtetracycline, in the 7,1la-positions by treatment withsuch halogenating agents as perchloryl fluoride, N-chlorsuccinimide, N-bromsuccinimide and iodobromide.

The present invention embraces all salts, including acidaddition andmetal salts, of the new antibiotics. Such salts are formed by well knownprocedures with both pharmaceutically acceptable and pharmaceuticallyunacceptable acids and metals. By pharmaceutically acceptable is meantthose salt-forming acids and metals which-do not substantially increasethe toxicity of the antibiotic.

The pharmaceuticallyacceptable acid addition salts are of particularvalue in therapy. These include salts of mineral acids such ashydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitricand sulfuric acids, as well as salts of organic acids such as tartaric,acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic,arylsulfonic, e.g. p-toluenesulfonic acids, and the like. Thepharmaceutically unacceptable acid addition salts, while not useful fortherapy, are valuable for isolation and purification of the newsubstances. Further, they are useful for the preparation ofpharmaceutically acceptable salts. Of this group, the more common saltsinclude those formed with hydrofluoric and perchloric acids.Hydrofluoride salts are particularly useful for the preparation of thepharmaceutically accept-able salts, e.g. the hydrochlorides, by solutionin hydrochloric acid and crystallization of the hydrochloride saltformed. The perchloric acid salts are useful for purification andcrystallization of the new products.

Whereas all metal salts may be prepared and are useful for variouspurposes,'thepharmaceutically acceptable metal salts are particularlyvaluable because of their utility in therapy. The pharmaceuticallyacceptable metals include more commonly sodium, potassium and alkalineearth metals of atomic number up to and including 20, i.e., magnesiumand calcium and additionally, aluminum, zinc, iron and manganese, amongothers. Of course, the metal salts include complex salts, i.e. metalchelates, which are well recognized in the tetracycline art. Thepharmaceutically unacceptable metal salts embrace'most commonly salts oflithium and of alkaline earth metals of atomic number greater than20,'i.e., barium and strontium, which are useful for isolating andpurifying the compounds.

It will be obvious that, in addition to their value in therapy,.thepharmaceutically acceptable acid and metal salts are also useful inisolation and purification.

The new tricyclic intermediates of the present invention, in addition totheir value in synthesis, exhibit valuable antimicrobial activity. Theymay be employed as bacteriostatic agents, and are further useful inseparation and classification of organisms for medical and diagnosticpurposes. These new intermediates, by virtue of their fi-diketonestructure, are also valuable chelating, complexing or sequesteringagents, and form particularly stable and soluble complexes withpolyvalent cations. They are therefore useful wherever removal of suchpolyvalent ions is desired, e.g., in biological experimentation and inanalytical procedures. Of course, as is wellknown to those skilled inthe'art, such fi-diketones may exist in one or more of severaltautomeric forms as a result of their abilityto enolize. It is fullyintended that the fi-diketone structures herein employed embrace suchtautomers.

The starting compounds of the present invention are readilypreparable'by known procedures. Many of these compounds, including bothbenzoic acid esters and benzophenone starting compounds, have beendescribed in the literature.

The following examples are given by way of illustration.

EXAMPLE I Monoethyl Ester of 3-(3-methoxybenzyl)Adipic Acid Method A:Five grams of diethyl 3-(3-methoxyben2oyl) adipate and 2 g. of 5%palladium on carbon in 30ml. of acetic acid are treated in aconventional Parr shaker at a pressure of 40 p.s.i. of hydrogen gas at50 C. until 2 moles of hydrogen are taken up. The first mole of gas istaken up rapidly and the second more slowly over a total reaction timeof up to about.30 hours. The mixture is filtered, concentrated underreduced pressure to an oil which is vacuum-distilled to obtain theproduct.

Method B: The 'y-lactone of the enol form of the monoethyl ester of thestarting compound is hydrogenated over palladium on carbon by this samemethod of obtain this product, b.pt. 190-1 C. (0.3 mm.). Elementalanalysis gives the following results:

Calcd. for C H O C, 65.29; H, 7.53. Found: C, 65.25; H, 7.68.

The corresponding diethyl-ester is prepared by refluxing this product inethylene dichloride containing ethanol and sulfuric acid. The diester isobtained by diluting the reactionmixture withwater, separating, dryingand concentrat ing the ethylene dichloride layer, and vacuum-distillingthe residual oil, n =l.4973. Elemental analysis gives the followingresults:

Calcd. for C H O C, 67.06; H, 8.13. Found: C, 67.02; H, 8.31.

Thestarting compound together with the corresponding 'ylactone are.prepared by hydrolysis and decarboxylation of diethyl3-carbo-t.-butoxy3-(3-methoxybenzoyl)adipate (Example XLV) by refluxingin dry xylene containing ptoluenesulfonic acid. Theproductsare separatedby fractional distillation or may be used together as starting compoundfor thishydrogenation reaction.

EXAMPLE II 3-(3-Methoxybenzyl)Adipic Acid Method A: Amalgamated zinc isprepared by shaking for 5 minutes a mixture of 120 g. of mossy zinc, 12g. of mercuric chloride, 200 ml. of water and 5 ml. of concentratedHClin a round bottomed-flask. Thesolution is decanted and the followingreagents added: ml. of water and 175 ml. of conc. HCl, ml. of tolueneand 52 g. .of 3-(3-methoxybenzozyl)adipic acid. The reaction mixture isvigorously boiled under reflux for 24 hours. Three 50 ml. portions ofconcentrated HCl are added at intervals of 6 hours during reflux.

After cooling to room temperature, the layers are sep arated, theaqueous layer diluted with 200 ml. of water and extracted with ether.The ether extract is combined with the toluene layer, dried andconcentrated under reducedpressureto obtain the product.

Method B: A solution of 6254.4 grams (22.1 mole) of3-(3-methoxybenzoyl)-adipie acid in 38.5 liters of glacial acetic acidis hydrogenated in a 15 gal. stirred autoclave inthe presence of 2.5 kg.5 percentpalladium-oncarbon catalyst at 1000 p.s.i.g. and 50 C. untilthe theoretical amount of hydrogen has been absorbed. The catalyst isfiltered off and the solvent removed from the filtrate by distillationat reduced pressure. This gives 5432 grams of product in the form of anoil. It is further purified by conversion to the dimethyl ester,fractional distillation, and hydrolysis, as follows:

A solution of 5432 grams (20.4 mole) of the crude 3-(3-methoxybenzyl)adipic acid, 3410 grams (106.6 mole) methanol, 10.6liters ethylenedichloride and 106 ml. concentrated sulfuric acid isstirred and refluxed for 15 hours. The mixture is cooled and washed withWater (3X 5 1.), 5 percent aqueous sodium hydroxide (1X 2 l.) and againwith water (3x 5 1.). The ethylenedichloride solution is dried over 3lb. anhydrous magnesium sulfate (with 2 lb. Dacro G60 activated carbon).The drying agent and carbon are filtered off and the filtrateconcentrated at reduced pressure to remove solvent. The residue isdistilled through a 3 x 16 vacuum-jacketed fractionating column packedwith porcelain saddles. After a forerun of 934.1 grams, the product iscollected at 172.0 C./0.2 mm. to 183 C./ 0.35 mm. This amounts to 3076.6g. of 95 percent pure ester.

The ester, 2943.4 grams (10.00 mole) is hydrolyzed by heating over asteam bath for 19 hours with 1 kg. (25.0 mole) sodium hydroxide in 6liters of water. The hydrolysis mixture is acidified to pH ca. 1.0 byaddition of concentrated hydrochloric acid and the product is extractedinto methylene chloride (1 X 41. and 2x 2 1.). The methylene chlorideextract is washed with water (1X 4 l.+1 8 1.), dried over magnesiumsulfate, filtered and freed of solvent by distillation at reducedpressure. This gives 2506 grams of 3-(3-methoxybenzyl)adipic acid in theform of a very sticky oil.

Method C: A solution of dimethyl 3-(3-methoxybenzyl) adipate (0.01 mole)in 280 ml. of 1:1 tetrahydrofuran:1,2- dimethoxyethane at a temperatureof about l C. is treated with a solution of sodium borohydride (0.005mole) in 30 ml. of 1,2-dimethoxyethane and 10 ml. of water. After 15minutes, ml. of glacial acetic acid is added and the mixture stirred for5 minutes. Hydrochloric acid (3 ml. of 6N) is then added, the mixturestirred for an additional 0.5 hour, then poured into water. The product,3 et-hydroxy- 3-methoxybenzyl) ]adipic acid dimethyl ester, is recoveredby evaporation.

The hydroxy ester is placed in 150 ml. of anhydrous hydrogen fluorideand allowed to stand overnight. The hydrogen fluoride is then evaporatedand the thus produced dimethyl 3-(3-methoxy benzylidene)adipatedissolved in dioxane (300 ml.), treated with 0.3 g. of palladium oncharcoal (5%) and subjected to 50 p.s.i. at room temperature until anequimolar proportion of hydrogen is consumed. The mixture is filteredand the filtrate evaporated to dryness under reduced pressure to givethe desired compound as the methyl ester. It is hydrolyzed 'to the acidby the procedure of Method B.

EXAMPLE III Dimethyl 3-(2-chloro-5-methoxybenzyl)adipate Method A: Amixture of 3.2 g. of dimethyl 3-(3-methoxybenzyl)adipate and 1.4 g. ofN-chlorosuccinimide in 30 ml. of trifluoracetic acid is stirred andheated on a steam bath for 30 minutes. The reaction mixture is thenpoured into 5% aqueous sodium bicarbonate with stirring, and the mixtureextracted with ether. The combined extracts are dried over anhydroussodium sulfate and then concentrated under reduced pressure to an oilwhich is vacuum-distilled to obtain the product, b.p. 200 C. (1.1 mm.Hg).

Method B: A mixture of 3.2 g. of dimethyl 3-(3-methoxybenzyl)adipate and2.1 g. of phosphorous pentachloride in 100 ml. of dry benzene isrefluxed for 30 minutes. The reaction mixture is carefully poured intoice and water, the benzene layer separated, washed with water and dried.Concentration of the dried benzene solution 20 under reduced pressureyields an oil which is vacuumdistilled to obtain the product.

Similarly, the diethyl, dibenzyl and dipropyl chloroesters are prepared.

Method C: A solution of 1688 g. of 3-(3-methoxybenzyl)adipic acid and 50mg. of iodine in 9 liters of glacial acetic acid is stirred while asolution of 450 g. of chlorine in 8 liters of glacial acetic acid isadded during about 2 hours. The mixture is kept in the dark during theprocedure and the temperature maintained at 10-l5 C. The solvent is thenremoved by concentration under reduced pressure to give 1902 g. of adark amber oil.

This procedure is repeated with ferric chloride in lieu of iodine withcomparable results.

Method D: A mixture of 30.4 g. of diethyl 3-(3-methoxybenzyl)adipate and12.75 g. of sulfate chloride in 250 ml. of benzene is allowed to standfor 3 days at room temperature. At the end of this period, the reactionmixture is concentrated under reduced pressure to a gummy residue whichis vacuum-distilled to obtain the product.

Method B: The procedure of Method B is repeated using as startingcompound the corresponding dicarboxylic acid to obtain3-(2-chloro-S-methoxybenzyl)- adipic acid dichloride.

EXAMPLE IV Diethyl 3- (2-ch1oro-5 -ethoxybenzyl adipate This product isobtained by the procedure of Method A of Example III employing diethyl3-(3-ethoxybenzyl)- adipate in lieu of dimethyl3-(3-methoxybenzyl)adipate.

EXAMPLE V 2- Z-Carbethoxyethyl -5-methoxy-8-chloro-4-tetralone Method A:A mixture of 2 g. of diethyl-3-(2-chloro-5- methoxybenzyDadipate(Example 111) and 30 g. of polyphosphoric acid is heated on a steam bathfor 30 minutes and then poured into ice water. The oil then separatesand is collected.

Method B: A mixture of 2.0 g. of the di-acid chloride of 3 (2 chloro 5methoxybenzyl) adipic acid in 30 ml. of carbon disulfide is cooled to 0C. and 4 g. of aluminum chloride added portionwise to the cooledmixture. The mixture is stirred for 30 minutes and then allowed to warmto room temperature where a vigorous reaction ensures. After thevigorous reaction subsides the mixture is warmed on a steam bath,cooled, diluted with Water and the carbon disulfide steam distilled. Themixture is extracted with chloroform and the product obtained by dryingand concentrating the chloroform extract. The product is the free acidwhich, if desired, is converted to the desired lower alkyl ester byconventional methods. For example, the methyl ester is prepared asfollows:

A mixture of 2002 g. (7.1 moles) of the tetralone acid, 3 l. chloroform,682 g. (21.3 mole) methanol and 21.2 ml. conc. sulfuric acid is refluxedwith stirring on a steam bath for 20 hours. The reaction mixture is thenchilled and 2 1. each of chloroform and water are added. The organicphase is separated and washed successively with two 2 1. water, one 1 l.2% aqueous sodium hydroxide and three 4 1. water to a final pH of about7.5. After drying over anhydrous sodium sulfate and treatment with DarcoKB activated carbon the solution is filtered and concentrated to a darkoil at reduced pressure. The oil is taken up in 6 1. hot ethyl acetateand 11 l. hexane add-- ed. The solution is chilled to 5 C. with stirringand 1404 g. 2 (2 carbomethoxyethyl) 5 methoxy 8- chloro -4 tetralonerecovered by filtration, hexane-washing and air-drying. The productmelts at 10l.0102.4 C.

EXAMPLE VI 2-(2-Carboxyethyl)-5-methoxy-8-chloro-4-tetralone Apolyethylene container is charged with 1809 g. (6.03 mole) 3 (2 chloro 5methoxybenzyl) adipic acid.

and chilled in an ice bath while 7 kg. liquid hydrogen fluoride isintroduced from an inverted, chilled tank. The mixture is swirled tomake homogeneous and then left to evaporate partially overnight in ahood. Most of the hydrogen fluoride that remains is removed by placingthe polyethylene container in warm water to cause rapid evaporation. Theremainder is removed by quenching in about 1. water. The product is thenextracted into chloroform, washed with water and dried over magnesiumsulfate. Removal of the drying agent by filtration and the solvent bydistillation gives a gum that is triturated with ether and filtered.This gives 1031 g. of crude product that is recrystallized from amixture of 16 1. ethanol, 2 l. acetone and 1 l. ethylene dichloride,with activated carbon treatment. The first 'two crops amount to 863.9grams, of white crystalline product melting at 175.0- 180.5 C.

Elemental analysis gives the following results: Calcd. for C H O Cl: C,59.47; H, 5.35; Cl, 12.54. Found: C, 59.51; H, 5.42; Cl, 12.60.

Ultraviolet absorption shows A max. at 223 m (e=24,650), 255 mu(e=7,900) and 326 mu (5:4,510). Infrared absorption maxima appear at5.76 and 599p.

This product is also obtained by hydrolysis of the product of Method A,Example V, by treatment with HCl in acetic acid.

The methyl ester, ethyl ester (m. 5759 C.) and benzyl ester (m. 8485 C.)are prepared by conventional methods.

3-(3-Methoxybenzyl)adipic acid, treated with HF as described, yields 2(2-marboxyethyl)-7-methoxy-4-tetralone, which melts at 158-9 -C. aftertwo recrystallizations from benzene-hexane and exhibits ultravioletabsorption maxima at 225 mu (e=13,500) and 276 m (6:16,- 000) inmethanolic HCl and NaOH.

Analysis, Calcd. for C H O C, 67.73; H, 6.50%. Found: C, 67.67; H.6.48%.

EXAMPLE VII 2- 2-Carb oxyethyl) -6-chloro-7-methoxy 4-tetralone Thissubstance is a byproduct of the cyclization of the products of ExampleIII. It is separated from the crude2-(Z-carboxyehtyl)-5-rnethoxy=8chloro 4 tetralone of Example VI byvirtue of its chloroform insolubility.

I 2900 g. of the crude tetralone are leached six times with 8 literportions of hot chloroform. 170 g. of white solid remain, melting at236239 C. The methyl ester is prepared by the procedure of Example V,Method B.

EXAMPLE VIII 2 (2 Carbomethoxyethyl) 5 benzyl0xy-8-chloro-4- tetralone2-(2-Carboxyethyl)-5-methoxy-8-chloro 4 tetralone g.), glacial aceticacid (200 ml.) and 48% hydrobromic acid (50 ml.) are heated at 90 undernitrogen for twenty-four hours. The cooled solution deposits acrystalline solid. The mixture is poured over two parts ice and thetotal solid crop isolated by filtration and thoroughly washed withWater. The crude 2-(2-carboxyethyl)-5-hydroxy-S-chloro 4 tetraloneobtained in this way is recrystallized from acetonitrile to obtain 18.8g. melting at 164-8 C.

Elemental analysis, Calcd. for C H ClO C, 58.11; H, 4.88; Cl, 13.20%.Found: C, 57.99; H, 4.87; Cl, 12.73%.

14.5 g. of this product is placed in 200 ml. dry methanol and themixture refluxed for minutes as anhydrous HCl is passed through. The nowclear yellow solution is allowed to stand overnight, and the methanol isthen removed in vacuo. The residual gum is extracted exhaustively withhexane and the combined extracts are concentrated and cooled. 11.8 g. ofthe white, crystalline methyl ester separates and is filtered oif andrecrystallized from 22 hexane. The ester melts at 6869.5 C. and analyzesas" follows:

Calcd. for C H CIO C, 59.45; H, 5.35; CI, 12.6%. Found: C, 59.16; H,538; C1, 12.6%.

5.6 g. (0.02 mole) of this substance is dissolved in 500 ml. anhydrousmethanol and to this is added 0.02 mole sodium methoxide and 500 ml.benzene. The mixture is concentrated to dryness in vacuo at roomtemperature, then heated at C. and 0.1 mm. for 10 minutes. The residueis maintained under high vacuum at room temperature for 16 hours, andthe dry solid added to 50 ml. benzyl bromide together with suflicientdimethyl formamide to solubilize. The mixture is heated at 100 C. for 48hours with stirring, then cooled and filtered. The filtrate isconcentrated at reduced pressure and the residual oil chromatographed onacetone-washed and driedsilicic acid in chloroform. The first effluentfraction consists of unchanged starting material. The main fraction,recognized by a negative ferric chloride test, deposits crystalline2-(2- carbomethoxy ethyl)-5-benzyloxy-8-chloro-4-tetralone on standing.

EXAMPLE IX 2 Carbomethoxy-5-methoxy-8-chloro 3,4,10 trioxo-1,2,3,4,4a,9,9a,10-octahydroanthracene 30 .Grams of2-(2-carbomethoxyethyl)-5-methoxy 8- chloro-4-tetralone (0.1 mole),prepared as described in Example V, Method B, is dissolved together with24 grams dimethyloxalate (0.2 mole) by warming with ml. freshlydistilled dimethyl formamide in a well dried two liter flask whichhas'been flushed with dry nitrogen. The solution is cooled to 20 C. andto it is added all at one time0.4 mole sodium hydride in the form of a50% oil dispersion which has been exposed to the atmosphere for 24 hoursin order to produce a deactivating coating. The reaction mixture ismaintained at 20-25 C. with an ice bath. 0.1 mole dry methanol is nowadded, and the temperature rises spontaneously to 4050 C. When thetemperature begins to fall (about 5 minutes after addition of themethanol) the reaction vessel is removed from the ice bath and quicklyplaced in an oil bath at 110 C. The reaction temperature is brought withdispatch to 90 C. and maintained there for 10 minutes, or until activebubbling ceases if this occurs sooner.

The flask is now immediately transferred back to the ice bath, and whenthe temperature reaches 15 C., 100 ml. of glacial acetic acid is addedat such a rate that the temperature does not exceed 30 C. At this point,a golden yellow precipitate appears. ml. methanol and 50 ml. water areadded and the mixture is digested at 45 C.'for 15 minutes and thenstirred in an ice bath for an hour. If only a scanty crop of crystals ispresent at this time the mixture may be stored in the refrigeratorovernight before proceeding. It is now transferred to a separatoryfunnel to permit separation of the oil from the sodium hydride oildispersion. The suspension is then filtered with suction, and the filtercake triturated three times with 100 ml. portions of hot hexane toextract impurities. The washed solid is next stirred with 200 ml. water,filtered, and then digested with 500 ml. refluxing methanol for 20minutes, to effect further purification. 15-16 grams of bright yellowneedles are obtained. The product melts at 200-205 C. and exhibits nocarbonyl absorption below 6,11. In 0.01 N methanolic HCl it exhibitsultraviolet absorption maxima at 406 mu (E: 14,200) and at 275-290 m(e=5,940). In 0.01 N methanolic NaOH it exhibits maxima at 423 m(e=13,950) and at 340 111,41. (e=7,120).

EXAMPLE X 2-carbomethoxy-6-chloro-7-methoxy-3,4, 10-trioxo- 1,2,3,4,4a,9,9a, l O-Octahydmanthracene 2 (2 carbomethoxyethyl) 6 chloro 7methoxy- 4-tetralone, prepared in Example VII, 30 g., is dissolved in 24g. dimethyl oxalate in 300 ml. dry distilled dimethyl formamide bywarming. The solution is then cooled under nitrogen in an ice-salt bathand 19.86 g. sodium hydride (51.2% in oil) added all at once as thetemperature is maintained below 20 C. The ice bath is removed and thetemperature rises spontaneously to 50 C., whereupon the bath is replacedbriefly to control the vigorous reaction. The reaction mixture is thenheated to 70-80 C. for 5-8 minutes, cooled to below C., and treated with100 ml. acetic acid, added at such rate that the temperature does notreach 25 C. The reaction mixture is now poured into four volumes ofchloroform. The chloroform solution is washed with water, then withsaturated brine, and dried over anhydrous sodium sulfate. The solvent isremoved in vacuo, and the residue is treated with 350 m1. methanol.After standing for several hours at room temperature the slurry isfiltered to obtain 12.5 g. yellow crystalline product, melting at228-231 C. with decomposition and gas evolution. Recrystallization fromchloroform-methanol raises the melting point to 235.6-236.8 C.

Analysis, Calcd. for C H O Cl: C, 58.21; H, 4.31; CI, 10.11%. Found: C,58.53; H, 4.43; Cl, 10.10%.

EXAMPLE XI Z-Carbobenzyloxy--methoxy-8-chloro-3,4,10-trioxo-1,2,3,4,4a,9,9a,10-octahydroanthracene 2 (2 Carboxyethyl) 5 methoxy 8chloro 4 tetralone, 0.02 mole, is combined with 500 ml. anhydrousmethanol and to this is added 0.02 mole sodium methoxide and 500 ml.benzene. The mixture is concentrated to dryness in vacuo at roomtemperature, then heated at 100 C. and 0.1 mm. for 10 minutes. Theresidue is maintained under high vacuum at room temperature for 16hours, and the dry solid added to 50 ml. benzyl bromide together withsufiicient dimethyl formamide to solubilize. The mixture is heated at100 C. for 48 hours with stirring, then cooled and filtered. Thefiltrate is concentrated under reduced pressure to obtain the benzylester as residue. Purification is effected by washing of a chloroformsolution with aqueous sodium bicarbonate.

This substance is dissolved together with 0.04 mole dibenzyl oxalate in50 ml. dry, distilled dimethyl formamide. To this is added 0.08 molesodium hydride in the form of a 50% oil dispersion, while maintainingthe temperature at about 20-25 C. Benzyl alcohol, 0.02 mole, is added,and the mixture is heated to 80 C. for 5 minutes, then cooled to 20 C.and slowly acidified with glacial acetic acid. The reaction mixture isnext evaporated to dryness under reduced pressure and the residue istaken up in chloroform. The chloroform solution is washed with water,then with brine, dried over sodium sulfate, treated with activatedcarbon and filtered. The filtrate is evaporated at reduced pressure toobtain the product as residue. It is purified by evaporation of thehighly fluorescent, less polar eluate fraction from silicic acidchromatography in chloroform.

EXAMPLE XII 2-Carbomethoxy-S-methoxy-8-chloro-3,4,10-trioxo-1,2,3,4,4a,9,9a, l0-octahydroanthracene Clean sodium metal (3.68 g.) isdissolved in methanol (50 ml.) and the solution evaporated to a drywhite solid in vacuo (this is most successfully carried out by usingrotary vacuum equipment). Dimethyloxalate (9.44 g.) and benzene (100ml.) are then added to the flask and refluxing is carried out for about10 minutes under nitrogen (not all of the solids dissolve but the cakeis broken up). The solution is cooled and dimethylformamide (50 ml.)then added followed by the dropwise addition of a solution of2-(2-carboxyethyl)-5-methoxy-8-chloro-4-tetralone (Example VI) (11.3 g.)in dimethylformamide (100 ml.) during one hour at 20" under N withstirring, and stirring at room temperature under N is continuedovernight. The solution is then poured into cold water l 1.) andextracted twice with chloroform. The chloroform extract is discarded andthe aqueous solution acidified with 10% HCl solution. The product isobtained by extraction with chloroform (3x 200 ml.), back-washing oncewith water, drying over anhydrous Na SO treatment with charcoal,filtration and evaporation of the solvent in vacuo to give a red gum(16.4 g.) which is 2-(2- carboxyethyl)-3-methyloxalyl-5 methoxy 9 chloro4- tetralone.

UV. absorption:

maxima in 0.01 N NaOH at 258 and 363 m maximum in 0.01 N HCl at 347 mminimum at The gum gives a deep red color with ferric chloride inmethanol and liberates CO from a saturated NaI-lCO solution.

The acid is esterified by dissolving in chloroform (1 1.), methanol ml.)and conc. H SO (10 ml.) and refluxing gently for 15 hours. The solutionis cooled, poured into excess water and the chloroform layer separated.The aqueous layer is extracted with chloroform (250 ml.) and thecombined chloroform extracts are backwashed twice with cold water. Theextract is then dried over anhydrous sodium sulphate, treated withactivated charcoal, filtered and evaporated to a red gum in vacuo. Thisgum does not liberate CO from saturated bicarbonate solution, and givesa deep red color with ferric chloride in methanol.

The ester product, 3.825 grams, and 1.275 g. of sodium hydride (56.5%solution in oil) are dissolved in 25 ml. of dimethylformamide. Anexothermic reaction sets in with the evolution of hydrogen gas. Afterthe evolution of gas ceases the mixture is warmed at 40 C. for /2 hourwhere further evolution of hydrogen gas occurs and the reaction mixturedarkens. The reaction mixture is finally digested on a steam bath for 10minutes after which it is cooled and acidified with glacial acetic acid(15 ml.). The product is then obtained by dilution of the mixture withwater followed by extraction with chloroform. The dried chloroformsolution is concentrated under reduced pressure to obtain a gummyresidue which crystallizes on trituration in methanol. The orange-yellowcrystalline product, 2-carbomethoxy-5-methoxy-8-chloro-3,4,lO-trioxo-1,2,3,4,4a,9,9a,10-octahydroanthracene, (1.2 g.) melts at196201.5 C.

EXAMPLE XIII 2-Carbomethoxy-5-hydroxy-8-chloro-3 ,4,10-trioxo-1,2,3,4,4a,9,9a,10-octahydroanthracene Dimethyl oxalate, 0.84 g., and2-(2-carbomethoxyethyl)-5-hydroxy-8-chloro-4-tetralone, 2.0 g., areadded to a suspension of 0.34 g. sodium hydride in 10 ml. dimethylformamide and the mixture is heated to C. for three minutes. Aftercooling, the reaction mixture is treated with 10 ml. acetic acid andevaporated to dryness at reduced pressure. The residual gum istriturated with water to remove sodium acetate and chromatographed onsilicic acid in chloroform. The main efiluent fraction is dried to abright yellow solid which is crystallized from chloroform-hexane toprovide 380 mg. product melting at 218 219.5 C. Elemental analysis,calculated for C H O Cl: C, 56.7; H, 3.9; Cl, 10.5; found: C, 56.86; H,3.89; Cl, 10.8%.

EXAMPLE XIV Diethyl 3- u-hydroxy-3-methoxybenzyl adipate This product isobtained by treating 5 g. diethyl 3-(3- methoxybenzoyl) adipate and 2 g.5% palladium on carbon in ethanol with 40 p.s.i. hydrogen gas at roomtemperature until one molar equivalent of hydrogen is consumed. Thereaction mixture is filtered and concentrated at reduced pressure toobtain the product.

It is further converted to diethyl3(iz-N,N-dimethylamino-3-methoxybenzyl)adipate in the following manner:

The a-hydroxy benzyl adipate ester, 0.01 mole in 15 ml.

dimethoxyethane, is added to a stirred mixture of 1.9 g. (0.01 mole)p-toluenesulfonyl chloride and 2.5 ml. dry pyridine in an ice bath. Whenthe reaction subsides the mixture is permitted to warm to roomtemperature, stirred for three hours, and poured into 50 ml. water. ThepH is adjusted to 5 and the resulting tosyl ester recovered byfiltration.

The tosylate (0.0025 mole) is combined with 25 ml. dimethoxyethaneandadded dropwise to a stirred solution of 0.015 mole dimethylamine in50 ml. dirnethoxyethane at C. After addition is complete, stirring iscontinued for an. hour at 0 and the reaction mixture is then heated at60 for three hours under a Dry Ice condenser. The mixture is nextevaporated in vacuo and the residue washed with water to removedimethylammonium toluenesulfonate. The product is recovered byfiltration from the water. Substitution of monomethylamine fordirnethylamine in this procedure provides the corresponding a-N-methylamino derivative.

EXAMPLE XV 2- Z-Carbomethoxyethyl -methoxy-4-tetral0ne 2-(2-Carbomethoxyethyl) 5 methoxy-8-chloro-4- tetralone (1.5 g.) is combinedwith 5% palladium-oncharcoal (0.37 .g.), triethylamine (0.5 g.) andmethanol 270 ml. in a standard Parr hydrogenation bottle and subjectedto 50 pounds of hydrogen pressure. The absorption of hydrogen levels offat approximately one molar equivalent. The catalyst is filtered off, thesolution taken to dryness, and triethylamine hydrochloride is removed bywashing with'water. The residual white solids weigh 1.1 g. and melt at63-66" C. After two recrystallizations from hexane and one from etherthe product melts at 8587.

Analysis.--Calcd. for C H O C, 68.68; H, 6.92%. Found: C, 68.59; H,6.98%.

EXAMPLE XVI 2- Z-Carboxyethyl -7-hydroxy-4-tetralone3-(3-methoxybenzyl).adipic acid, 22.46 g., is heated at reflux withhydriodic acid (specific gravity 1.5) for 3 hours and the methyl iodideformed is separated. The solution is evaporated in vacuo and theresulting gum triturated with cold water to yield 14.7 g. of yellowcrystalline product. Dried and recrystallized from aqueous acetone theproduct is obtained in the form of white crystals melting at 183.5185.5C. Elemental analysis, calculated for C13H14O4: C, 66.65; H, 6.02;found: C, 66.60; H, 6.02%.

The same. productis obtained by refluxing a mixture of 0.5 g. of the3-(3methoxybenzyladipic acid with 25 ml. 48% HBr for 18 hours, thenpouring the reaction mixture into 3 volumes of water, and filtering theresulting 0.4 g. of crystalline precipitate.

EXAMPLE XVII 2- (2-Carb0methoxyethyl -5-methoXy-8-nitro-4- tetralone Onegram of the Example XV product is slowly added to ml.-of= concentratedsulfuric acid containing 2 ml. of 70% nitric acid at a temperature of05C. The solution is stirredfor minutes and allowed to warm to roomtemperature. The mixture is poured into ice-Water mixture and extractedwith chloroform, the chloroform layer separated, dried and concentratedto obtain the product. 7

EXAMPLE XVIII 2- (Z-Carboxyethyl) -S-hydroxy-8-amino-4-tetralone Onemolecular proportion of aniline is dissolved in 2N HCl, employing aboutml. thereof per gram of aniline, and the solution treated with onemolecular proportion of NaNO at 0 to 10 C. The benzenediazonium chloridesolution is then mixed with stirring at 0 to 20 C. with an aqueoussolution of 2-(2-carboxyethyl)-5-hydroxy-4- tetralone sodium salt andsufficient sodium carbonate to neutralize the excess HCl in thediazotised aniline solution. The pH of the solution is in the range8-10. Stirring is continued at 0 C. for approximately two hours afterwhich careful neutralization of the reaction mixture yields theS-phenylazo compound. The product is collected on a filter, washed anddried.

One part by weight of 2-(Z-carboxyethyl)-5-hydroxy-8-phenylazo-4-tetralone is mixed with 20 parts by weight of methanol and/5 part by weight of 5% palladium-on-carbon catalyst is added to themixture which is then hydrogenated at 30-45 p.s.i. of hydrogen gas in aconventional shaker apparatus at 30 C. until two molar equivalents ofhydrogen are taken up.

After filtration, the product is recovered by high Vacuum distillationof the residue obtained by removal of the solvent in vacuo. Care must beexercised to protect the amino phenol from air. It'can be stabilized byacetylation, as follows:

The crude amine is placed in 20 parts water containing one molarequivalent of HCl, and 2.2 molar equivalents of acetic anhydride areadded. Sufiicient sodium acetate is then added to neutralize the HCl andthe solution is warmed to 50 C. After 5 minutes the mixture is cooledand the crude acetate separated by filtration. The solid is thendissolved in cold 5% sodium carbonate solution and reprecipitated with5% HCl. The 2-(2-carboxyethyl)-5- hydroxy-8-N-acetylamino 4 tetraloneobtained in this manner is a preferred form of the amino compound forfurther reaction sequences.

EXAMPLE XIX 3- (2-Amino-5-hydroxybenzyl)adipic acid The procedure ofExample XVIII is repeated using 3- (3-hydroxybenzyl)adipic acid asstarting compound to obtain this product. It may be converted to theproduct of Example XVIII by the ring closure procedure of Example VI.

EXAMPLE XX 3- 2-Chloro-5-hydroxybenzyl) adipic acid Three parts byweight of the product of Example XIX (obtained by evaporating themethanol) is protected from air, immediately mixed with 10 parts byweight of 10% aqueous hydrochloricacid at 0 C., and diazotized bygradual addition of 20% aqueous sodium nitrile solution. Addition ofsodium nitrite is continued until a positive starch iodide test on a fewdrops of the reaction mixture is obtained in the conventional fashion.The resulting solution is then added to 15 parts of a boiling 10%solution of cuprous chloride in aqueous hydrochloric acid. The mixtureis boiled for 10 minutes and allowed to cool. The product separates fromthe cooled mixture and is col lected in the conventional manner.

This procedure is used for the preparation of3-(2-substituted-5-hydroxy-benzyl) adipic acid compounds such as Z-bromo(using Cu Br and HBr), 2-iodo (using KI and H 50 EXAMPLE XXI 3-[tX-HydI'OXy-OL- (2-chloro-S-methoxy-phenyl) ethyl] adipic acid diethylester To a solution of 3-(2-chloro-5-methoxybenzoyl)adipic acid diethylester in dimethoxyethane is added dimethoxyethane solution containing amolar equivalent of methyl magnesium bromide. After standing for 30minutes, the reaction mixture is acidified cautiously with ice andaqueous 6N HCl, and extracted with methylene chloride. The extracts arecombined, washed with water, dilute aqueous sodium bicarbonate andwater, dried and concentrated under reduced pressure to obtain theproduct.

EXAMPLE XXII 3- [a- 2-Chloro-5-methoxyphenyl) ethyl] adipic acid diethylester The product of Example XXI, 2 g., is dissolved in 150 ml. ofglacial acetic acid and hydrogenated at a pressure of 40 p.s.i. ofhydrogen gas for 24 hours at room temperature in the presence of 2 g. of5% palladium-on-carbon catalyst. The mixture is filtered and thenconcentrated. The product is obtained by vacuum distillation of theresidue.

EXAMPLE XXIII 3 ,3 ,4-Trimethoxybenzophenone A mixture of 40 g. of3-methoxybenzoyl chloride, 32 g. of vertrole and 250 ml. of carbondisulfide in a 3 neck round bottom flask fitted with reflux and stirreris cooled to C. Then 40 g. of aluminum chloride is added portionwise tothe cooled mixture and the mixture stirred for 45 minutes, after whichit is allowed to warm to room temperature. A vigorous reaction ensueswith the separation of a yellow precipitate. The mixture is carefullywarmed on a steam bath and stirred for 1 /2 hours. Water is then addedto the cooled mixture and the carbon disulfide is steam distilled oif.The resultant mixture is then extracted with chloroform and thechloroform layer separated, washed with dilute hydrochloric acid,followed by dilute sodium hydroxide and then dried and concentratedunder reduced pressure. The residual oil is distilled to obtain theproduct, b.p. 2162l8 C. at 1.5 mm. mercury. A 65% yield of product isobtained. The viscous product is stirred in absolute methanol andcrystallizes, m.: 85- 86 C.

EXAMPLE XXIV 3,3 ',4-Trimethoxydiphenylmeth ane Method A: A solution ofg. of 3,3',4-trimethoxybenzophenone in 200 ml. of ethanol containing 1g. of copper chromium oxide is hydrogenated at 180 C. and 100atmospheres of hydrogen gas for 1.5 hours. The resultant solution isfiltered and concentrated under reduced pressure. The residual oil isdistilled to obtain the product b.p. 192194 C. at 2.5 mm. mercury. Theproduct crystallizes on standing, the melting point of the crystalsbeing 4546 C. Elemental analysis gives the following results:

Calcd. for C H O C, 74.39; H, 7.02. Found: C, 74.50; H, 7.18.

Method B: This product is also obtained by hydrogenation of the startingcompound of Method A using palladium on carbon in ethanol at 50 C. and40 p.s.i. of hydrogen gas. The hydrogenation procedure is also carriedout at room temperature, although the uptake of hydrogen is considerablyslower than at 5 0 C. The product is obtained by filtration andconcentration of the hydrogenation mixture.

EXAMPLE XXV 3,34-Trihydroxydiphenylmethane Two grams of3,3'4-trimethoxydiphenylmethane are dissolved in 10 ml. of acetic acidand 10 ml. of 48% hydrobromic acid and the mixture refluxed for 5 hours.The reaction mixture is concentrated under reduced pressure to obtain aresidual gum which is vacuum-distilled (b.p. 230 C. at 0.5 mm. ofmercury). The distillate, a colorless gum, crystallizes. A 62% yield ofproduct is obtained, m. 103.5104 C.

EXAMPLE XXVI 3- 3-Hydroxybenzyl -hexa-2-4-di-enedioic acid A mixture of3.5 g. of 3,3'4-trihydroxydiphenylmethane in 50 ml. of acetone and 50ml. of 10% aqueous sodium hydroxide is cooled to 0 C. Thirty ml. of 35%aqueous hydrogen peroxide solution is then added dropwise, the mixtureturning pale pink after 5 to 10 minutes. An exo- 28 thermic reactionoccurs with considerable boiling and foaming. The mixture is allowed tostand for 1 hour and is then extracted with ethyl acetate, the extractbeing discarded. The aqueous solution is then acidified and extractedwith ethyl acetate. Concentration of the ethanol acetate extract afterdrying gives the product as a gummy residue.

EXAMPLE XXVII 3- 3-Hydroxybenzyl adipic acid The product of thepreceding example (105 mg.) is dissolved in 13 ml. of ethanol containing1 drop of concentrated hydrochloric acid and hydrogenated over platinumoxide at 1 atmosphere of hydrogen gas at room temperature. The hydrogenuptake is exactly 2 molecular equivalents. Filtration and concentrationof reaction mixture gives the product.

EXAMPLE XXVIII 3-(3-Methoxybenzyl)adipic acid dimethyl ester The acidproduct of the preceding example is dissolved in aqueous sodiumhydroxide (4 molar equivalents) and agitated with 3 molar equivalents ofdimethyl sulfate at 40 C. for 6 hours. The resultant solution is thendiluted with Water and extracted with chloroform. The chloroform layeris separated, dried and concentrated under reduced pressure to yield anoil, b.p. 205 to 210 C. at 0.2 mm. mercury. This product is alsoobtained by treatment of the starting compound with diazomethane indiethyl ether.

In a similar manner the corresponding ethyl and propyl esters areprepared.

EXAMPLE XXIX 3-(3-Methoxybenzyl)hexa-2,4-dienedioic acid Five grams of3,3'4-trimethoxydiphenylmethane are dissolved in ml. of acetic acidcontaining about 10 drops of water and ozonized air containing about 4%O is then passed into the mixture for 1.5 hours (total of about 6 molesof ozone). The resultant yellow solution is poured into 1 liter of waterand extracted with chloroform. The chloroform layer is separated, washedwith aqueous sodium bicarbonate solution and concentrated under reducedpressure. The residue is dissolved in ethanol containing 2 g. of KOH andthe mixture allowed to stand at room temperature for 2 days after whichit is diluted with Water and extracted with chloroform. After separationof the chloroform layer the aqueous alkaline solution is acidified withdilute hydrochloric acid and extracted with chloroform. Concentration ofthe chloroform extract gives the acid product. 7

The methyl, ethyl and propyl diesters of this acid are prepared byrefluxing the acid for 3 days in ethylene dichloride containing theappropriate alcohol and sulfuric acid.

EXAMPLE m 3-(3-Methoxybenzyl)adipic acid dimethyl ester The ester of thepreceding example is hydrogenated in ethanol over 10% palladium oncarbon at 1 atmosphere of hydrogen gas at room temperature. Thetheoretical uptake of hydrogen gas (2 molar equivalents) is very rapid.The product is obtained by filtration and concentration of thehydrogenation mixture.

In similar fashion the corresponding free acid is obtained byhydrogenation of the free acid of the preceding example.

EXAMPLE XXXI The following monoester compounds are prepared by reductionof corresponding benzoyl diesters according to the methods of Example I.The free adipic acid derivatives are prepared by the methods of ExampleII from the corresponding benzoyl adipic acids. The products are subse-3-benzyladipic acid monoethyl ester 3-(2-ethy1-5-hydroxybenzyl) adipicacid monoethyl ester 3-(Z-chloro-S-methoxybenzyl) adipic acid monomethylester 3-(2-dimethylamino-S-methoxybenzyl)adipic acid monomethyl ester 3-Z-amino-S-methoxybenzyl) adipic acid3-(2-acetamido-S-methoxybenzyl)adipic acid 3-(3-hydroxy-benzyl)adipicacid monoethyl ester 3-(3-methyl-S-hydroxybenzyl)adipic acid monoethylester 3-(2,3-dimethyl-5-hydroxybenzyl)adipic acid monoethyl ester 3(2-methyl-5 hydroxybenzyl)adipic acid monoethyl ester3-(3-dimethylan1ino-S-hydroxybenzyl)adipic acid monoethyl ester,

3-(2,3-dimethylbenzyl)adipic acid monomethyl ester3-(3,5-dimethoxybenzyl)adipic acid monoethyl ester3-(3-hydroxybenzyl)adipic acid monoethyl ester3-(3-isopr0pyl-5-hydroxybenzyl)adipic acid monoethyl ester3-(2,3-diethyl-S-hydroxybenzyl)adipic acid monoethyl ester3-(S-benzyloxybenzyl)adipic acid monoethyl ester3-(2-chloro-S-benzyloxybenzyl) adipic acid monoethyl ester3-(S-propionyloxybenzyl)adipic acid monoethyl ester3-(3-acetyloxybenzy1)adipic acid monoethyl ester3-(Z-arnino-S-benzyloxybenzyl)adipic acid monobenzyl ester3-(2-propyl5-propoxybenzyl)adipic acid monomethyl ester3-(S-methoxy-Z,3-ditrifluoromethylbenzyl)adipic acid monomethyl ester3-(2-trifiuoromethyl-3,S-dibutoxybenzyl) adipic acid monoethyl ester 3-2-trifiuoromethyl-3-ethylamino-5-methoxybenzyl) adipic acid monoethylester 3-(3-butyrylamidobenzyl)adipic acid monoethyl ester3-(Z-trifiuoromethyl-S-hydroxybenzyl)adipic acid monobenzyl ester3-(2-chloro-5-hydroxybenzyl)adipic acid monobenzyl ester 3-2-chloro-3-rnethyl-S-hydroxybenzyl) adipic acid monoethyl ester3-(2-chloro-3-isopropyl-S-hydroxybenzyl)adipic acid monoethyl ester 3-2-chloro-3-amino-5-methoxybenzyl) adipic acid monoethyl ester 3-2-chloro-3-methyl-5-methoxybenzyl) adipic acid monobenzyl ester3-(2-chloro-3-ethyl-S-methoxybenzyl)adipic acid monobenzyl ester 3-(2-chloro-3-dimethylamino-5-hydroxybenzyl) adipic acid3-(3,S-dimethoxybenzyl)adipic acid monoethyl ester3-(Z-methylamino-S-propoxybenzyl)adipic acid monoethyl ester 3-Z-methyl-S-hydroxybenzyl) adipic acid3-(2-amino-5-benzyloxybenzyl)adipic acid monomethyl ester3-(3-acetamido-S-hydroxybenzyl)adipic acid monoethyl ester3(2-chloro-3,5-dihydroxybenzyl)adipic acid monoethyl ester3-(3-trifiuoromethyl-S-hydroxybenzyl)adipic acid monoethyl ester3-(3-hydroxybenzyl)adipic acid monoethyl ester The correspondingdiesters are prepared by esterification of these compounds with theselected alcohol by the usual method.

30 Those compounds having a benzyloxy substituent are reduced by theprocedures of Methods A or C of Example II. Of course, the procedure ofExample II, Method A, results in hydrolysis of the ester groups andnecessitates re-esterification.

EXAMPLE XXXII Alpha-hydroxybenzyladipic acid compounds corresponding tothe productsof Example XXXI are prepared by hydrogenation ofcorresponding benzoyladipic acid compounds according to the Method ofExample XIV.

The a-hydroxybenzyl adipate diesters are further converted to thecorresponding a-dimethylamino and amonomethylamino derivatives via thetosylates by the pr0- cedure described in Example XIV. For thisprocedure hydroxy substituents other than the a-hydroxy group areavoided by employing the corresponding methyl ethers; likewise, aminosubstituents are employed in acetylated form.

The tit-amino benzyl adipates obtained in this manner are furtherconverted to the corresponding l-amino-4-tetralones of structure III bythe procedure of Example VI.

EXAMPLE XXXIII The procedure of Example XXI is repeated to produce thefollowing compounds from corresponding benzoyladipic acid compoundsusing lower alkylmagnesium halides.

diethyl 3(a-hydroxy-a-phenethyl) adipate diethyl 3- [a-hydroxy-o-Z-ethyl-S-hydroxyphenyl ethyl] adipate dimethyl 3 OL-hYdI'OXY-Ot-(Z-dimethylamino-S-methoxyphenyl ethyl] adipate dimethyl 3-[cL-hYdIOXY-oc- (2-amino-5-methoxyphenyl) ethyl] adipate dimethyl 3-[-ot-hydroxy-a- (2-acetamido-5-methoxyphenyl )ethyl] adipate diethyl 3-[tX-hydIOXY-OL- 3-hydroxyphenyl ethyl] adipate diethyl 3- [cc-hYdrOXY-a-(2-chloro-5-methoxyphenyl) ethyl] adipate diethyl 3- oc-hYClTOXY-u- (3-methyl-5-hydroxyphenyl) ethyl] adipate diethyl 3- [a-hydroxy-u- 3,S-dimethoxyphenyl ethyl] adipate diethyl 3 [a-hydroxy-a- 3-methoxyphenyl) propyl] adipate diethyl 3- [cz-hYdIOXY-oc-(2-chloro-5-methoxyphenyl) propyl] adipate diethyl 3 [u-hydroxy-a-2-chloro-5 -methoxyphenyl) butyl] adipate diethyl 3 -[a-hydroxy-a- (3-methoxyphenyl) ethyl] adipate In the case of the precursors to thecompounds listed above which possess an active hydrogen, 2.5 moles ofGrignard reagent are employed.

The compounds containing an amino-substituent are isolated from thereaction mixture by the substitution of saturated aqueous ammoniumchloride for 6N I-ICl.

EXAMPLE XXXIV The a-hydroxy group of Example XXXIII compounds ishydrogenolyzed according to the method of Example XXII to alford thefollowing compounds:

diethyl 3- u-phenethyl adipate diethyl 3 oc- (Z-ethyI-S-hydroxyphenyl)ethyl] adipate dimethyl 3- [oc- (2-chloro-5-methoxyphenyl) ethyl]adipate dimethyl 3- [oz- (2-dimethylamino-S-methoxyphenyl) ethyl]adipate dimethyl 3- [Z-amino-S-methoxyphenyl) ethyl] adipate dimethyl 3-OL- (2-acetamido-S-methoxyphenyl) propyl] adipate diethyl 3 [a- (3-hydroxyphenyl) ethyl] adip ate diethyl 3- ['oc-3-methyl-5-hydroxyphenyl) ethyl] adipate 31 diethyl 3- [IX' (3 ,5-dimethoxyphenyl) ethyl] adipate diethyl 3- [a- 3-methoxyphenyl propyl]adipate diethyl 3- [a-Z-chloro-S-methoxyphenyl propyl] adipate diethyl3-[a-2-chloro-5-methoxyphenyl)butyl] adipate diethyl 3-[a-3-methoxyphenyl) ethyl] adipate EXAMPLE XXXV The following compoundsare prepared according to the methods of Example VI by ring closure ofcorresponding compounds.

2- Z-carbethoxyethyl -4-tetralone 2- 2-cyanoethyl-5-methoxy-8-ethyl-4-tetralone 2- 2-carboxyethyl -5-methoxy-8-dimethylamino-4- tetralone 2- 2-carb obenzyloxyethyl-5-methoXy-8-amino-4- tetralone 2-( 'Z-carbopropoxyethyl-5-methoxy-8-acetamido-4- tetralone 2- 2-carbobenzyloxyethyl-5-hydroxy-8chloro-4- tetralone 2- 2-carbethoxyethyl-5-hydroxy-7-methyl-8-chloro-4- tetralone 2- 2-carboxyethyl-5-hydroxy-7-isopropyl-8-ch10ro-4- tetralone 2- 2-carboxyethvl-5-hydroxy-7, 8-diethyl-4-tetralone 2- Z-carbethoxyethyl-5-propoxy-8-methylamino -4- tetralone 2- 2-carbobenzyl0xyethyl)-5-benzyloxy-8-chloro-4- tetralone 2- 2-carboxypropyl-S-hydroxy-S-chloro-4-tetralone 2- Z-carboxybutyl-S-hydroxy-8-chloro-4-tetralone 2- 2-carbobenzyloxyethyl-5-methoxy7-amino-S-chloro- 4-tetralone 2- 2-carbobenzyloxyethyl)-5-methoxy-7-ethyl-8-chlor0- 4-tetralone 2- Z-carbobenzyloxyethyl-5-methoxy-7-methyl-8-chl0ro- 4-tetralone 2- 2-carb oxyethyl-5-hydroxy-7-dimethylamino-8-chloro- 4-tetralone 2- Z-carboxyethyl-7,8-dimethyl-4-tetralone 2- Z-carboxyethyl-5-hydroxy-8-chloro-4-tetralone l-methyl-Z- 2-carboxyethyl-5-methoxy-8-chloro-4- tetralone1-ethyl-2-(2-carboxyethyl)-5-methoxy-8-chloro-4- tetralone 1-propyl2-2-carboxyethyl -5-methoxy-8-chloro-4 tetralone 1-methyl2-Z-carboxypropyl -5-methoxy-8-chloro-4- tetralone 2- Z-carboxyethyl-5-hydroxy-8-methyl-4-tetralone 2- 2-carboxyethyl) -5-hydroxy-7,8-dimethyl-4-tetralone 1-propyl-2- (-2-carboxyethyl)-5-hydroxy-8-chloro-4 tetralone 2- Z-cyanoethyl-5-methoxy-8-methyl-4-tetralone 2- Z-carboxyethyl-5-methoxy-7-methyl-8-chloro-4- tetralone 2 Z-carbethoxyethyl)-5,7-dimethoxy-4-tetralone 2- Z-carbobenzyloxyethyl-5-hydroxy-7-isopropyl-4- tetralone 2- Z-carbomethoxyethyl-5-benZyloxy-8-amino-4- tetralone 2- Z-carbomethoxyethyl-5-propoxy-8-propyl-4- tetralone 2- 2-carbomethoxyethyl-5-hydroxy-4-tetralone 1-methyl-2- 2-carbomethoxyethyl -5-methoxy-4-tetralone l-ethyl-Z- 2-carbomethoxyethyl -5-methoxy-4-tetralone1-propyl-2 Z-carbomethoxyethyl -5-methoxy-4-tetralone 2-Z-carbobenzyloxyethyl -5-hydr0xy-8-methyl-4- tetralone 2-2-carbobenzyloxyethyl )-5-methoxy-4-tetralone l-methyl-Z-Z-carbobenzyloxyethyl) -5-hydroxy-4- tetralone l-propyl-Z-Z-narbobenzyloxyethyl -S-hydroxy-4-tetralone 1-ethyl-2-2-carbobenzyloxyethyl) -5-methoxy-4-tetralone l-ethoxyethyl-Z-Z-carbethoxyethyl -7-propionyloxy-8- methyl-4-tetralone 1-ethyl-2-2-carbomethoxyethyl -5-ethoxy-7-acetoxy-8- chloro-4-tetralone 2- (Z-carbomethoxyethyl -7,8-ditrifiuoromethyl-S- methoxy-4-tetralone 2-(Z-carbethoxyethyl) -5,7-dibutoxy-8-trifluoromethyl-4- tetralone 2'Z-carbethoxyethyl -5-methoxy-7-ethylamino8-trifluoromethyl-4-tetralone2- Z-carbomethoxyethyl) -7-butyrylamido-4-tetralone 2-(2-carbobenzyloxyethyl -5-hydroxy-8-trifluoromethyl- 4-tetralone 2-Z-carbethoxyethyl -5,7-dihydroxy-8-chloro-4-tetralone 2-2-carbethoxyethyl) -5-hydr0xy-7- acetamido-4-tetralone 2-2-carbethoxyethyl) -S-hydroxy-7-trifiuoromethyl-4- tetralone 1-methyl-2-(Z-carbethoxyethyl -7-hydroxy-4-tetralone 2-( Z-carbobenzyloxyethyl-5-benzyloxy-4-tetralone 2- 2-carbethoxyethyl) -5'hydroxy-4-tetralone 2-2-carbobenzyloxyethyl) -5-rnethoxy-7-amino-4- tetralone 2-2-carbobenzyloxyethyl) -5 -methoxy-7-propyl-4- tetralone 2-Z-carbobenzyloxyethyl -5-methoxy-7-methyl-4- tetralone 2-2-carbobenzyloxyethyl -5hydroxy-7-dimethylamino- 4-tetralone l-methyl-Z-2-carbobenzyloxyethyl -5-methoxy-4- tetralone 1-ethyl-2-2-carbobenzyloxyethyl) -5-methoxy-4-tetralone 1-propyl-2-Z-carbobenzyloxyethyl) -S-methoxy-4- tetralone 2- 2-carbobenzyloxyethyl-8-trifiuoromethyl-4-tetralone 2- 2-carbobenzyloxyethyl)-5-benzyloxy-8-chloro-4- tetralone 2- Z-carbobenzyloxyethyl-5-methoxy-7-ethyl-4-tetralone 2-( 2-carbobutoxyethyl)-7-methoxy-8-chloro-4-tetralone 2- Z-carbomethoxyethyl-5-methoxy-7-acetamido-8- chloro-4-tetralone1-methyl-2-(Z-carbethoxyethyl)-8-trifluoromethyl-4- tetralone1-methyl-2- Z-carbethoxyethyl -5-methoxy-8-trifluoromethyl-4-tetralone1-methyl-2- Z-carbobenzyloxyethyl -5-ethoxy-4-tetralone 2-(Z-carbomethoxyethyl -5-methoxy-4-tetralone The aromatic chlorocompounds can be subsequently hydrogenolyzed to the correspondingdeschloro compounds by the procedure of Example XV.

Those compounds of the above list which contain no amino or hydroxygroups are also prepared by the methods of Example V.

EXAMPLE XXVI Example XXXV products and other analogous products preparedas described herein, as lower alkyl or benzyl esters or nitrile, arecondensed with diethyl oxalate according to the method of Example IX toobtain 3,4,10- trioxoanthracene derivatives. Those compounds having anactive hydrogen require the use of an additional mole of sodium hydride.

The reaction mixtures are worked up as follows: After 10 minutes, orwhen active bubbling ceases if this occurs sooner, the reaction mixtureis chilled to 15 C. and carefully acidified with glacial acetic acid.The dimethyl formided and excess acetic acid are then removed in vacuoand the residue partitioned between water and chloroform. The aqueousphase is re-extracted with chloroform, the combined chloroform extractstreated with activated carbon, dried, and filtered. The chloroformsolution is chromatographed on silicic acid or acid-washed Florisil. Thehighly fluorescent product fraction is collected and evaporated toobtain the desired substance.

5-0 CHzCgHs 5-0 CHzCaHs Method B: The Z-carbobenzyloxy compound (5 g.).

'In the above table, Me=CH Et=C H Pr=C H Bz='benzyl. Ether substituentsare converted to hydroxy corresponding to that of Example XII istreatedwith hy groups by HBr cleavage; and acylamido to amino groupsdrogen gas at room temperature in acetic acidand in. by hydrolysis. thepresence of 0.5 g. of 5% palladium on carbonrat EX'A'MPLEXXXVH 60p.s.i.g. until one molar equivalent of gas is taken up. 5 MethOXy 8ch1OrO 3,410 trioXO 1 ,2344a:,9,9a,10 The pIOdIJCFiS ObtainedfiltratiOl'l and Concentration octahydmanthracene of the reactionmlxture after warming to C. for 20 Method A: A mixture .of 10 g. of theester .productof Example XII, 250ml. of glacial acetic acid, 125 ml.cone. HCl and 25 .ml. of water is heated at 95 C. for 1 hour.

minutes to ensurecornplete evolution ofcarbon dioxide.

Method C: The product of Example XII (3 g.) is refiuxed for 3 hours in10 ml. of acetic acid, 10 ml. of con- Durin 'thefirst 45 minutesconsiderable elfervescence .occentrated Su.1func' acld and J W curs aiidithe suspended; matter gradually dissolves to give h1moformIS'addQdT'tOfthe fi p l Poul-ed a deep red-brown solution. The reactionmixture is then mto'excess' Water m l W F F FEQ poured into 2 liters ofcold Water and extracted with of the chloroform'dayer"'washmg! drymgever; Sd1um chloroform. The combined extracts are washedwith water,

sulfate and concentration. A solid residue is obtained andrecrystallized from methanol.

decolorizedwith activated carbon, dried and evaporated to anorange-crystalline solid (6.9 g.) which melts at If desired, furtherpurification is achieved by chro- 1'7 1 172,3 C; After recrystallizationfrom acetone-hexmatography on- 'silicic acid with -chloroform eliitiom'The ane, the product melts at 172-173" C. product is contained in theless polar -'filuentfraction.

37 is washed with hexane and distilled in vacuowto obtain 10.57- g.oflthe methyl ester product, b.p. 128131 C./ (0.5 mm.), n =1.5428.Infrared analysis shows characteristic peaks at 5.73 and 5.92;.

Elementalanalysis gives the following results: Calcd. for C H O C,63.45; H, 5.81. Found: C, 63.28; H, 5.89.

The ethyl and propyl esters are prepared in the same manner (but heatingat 50 C. for 15 minutes to insure complete reaction) using ethyl orpropyl acetate in lieu of methyl acetate.

EXAMPLE XLI t-Butyl ester of (3-methoxybenzoyl)acetic acid To a stirredsuspension of sodamide in liquid ammonia (prepared from 11.5 g. ofsodium in 400 ml. of liquid ammonia) is added 54 g. of t-butyl acetatein 50 ml. of dry ether followed by a solution of 41.5 g. of methyl-3-methoxybenzoate in 50 ml. of dry ether.'The ammonia is then replacedby 100 ml. of ether and the mixture refiuxed for 2 hours. After standingat room temperature for 12 hours, the mixture is poured into 400 ml. ofice water containing 28.8 ml. of acetic acid. The mixture is thenextracted with ether, the etherate washed with 2% sodium bicarbonatesolution and then dried over anhydrous sodium sulfate. After removal ofthe ether at reduced pressure, the residual oil is distilled in vacuo toobtain 33.5 g. of product, b.p. 126-l28 (0.3 mm.). Infrared absorptionof the product shows characteristic maxima at 5.75 and 5.90.

EXAMPLE XLII Ethyl 3-carbomethoxy-3- 3-methoxybenzoyl) propionate MethodA: To a suspension of 26 g. of sodium hydride in 250 ml. of drydimethylformamide is added dropwise with stirring at room temperature asolution of 108 g. of the Example XL methyl ester in 250 ml. of drydimethylformamide over a period of 45 minutes. The mixture is stirredfor an additional 30 minutes and there is then added dropwise withstirring a solution of 104 g. of ethyl bromoacetate in 250 ml. of drydimethylformamide. The mixture is allowed to stand for 12 hours and isthen evaporated under reduced pressure. The residual oil'is dissolvedin'chloroform and the solid-sodium bromine filtered. The chloroformsolution, after waterwashingand drying over sodium sulfate, isevaporated and the residual oil distilledin vacuo to obtain 112.5 g. ofproduct, b.p. 182-188" C. (1.4-1.5 mm). Infrared analysis of the.product shows characteristic peaks at 5.75 and 5.91 microns.

Elemental analysis gives the following results: Calcd. for C H O C,61.21; H, 6.17. Found: C, 61.39; H, 6.23.

Ethyl and propyl 3-carbethoxy-3-(3-methoxybenzoyl) propionate areprepared in similar fashion.

Method B: To amixture of 29' g. of methyl 3-'methoxybenzoate and 15 g.of sodium hydride in 75 m1. of dry dimethylformamide is added a solutionof 19 g. of dimethylsuccin ate in 175 ml. of the same solvent dropwisewith stirringat room temperature during 12-14 hours. The mixture iscarefully acidified with 25 ml. of acetic acid and stirred at'roomtemperature for an additional 3 hours. The filtered reaction mixture isnext evaporated to a residue consisting of an oil and solid which istreated with ether to dissolve the oil. The ether solution is filteredand. evaporated under reduced pressure to yield 18.29 g. of dimethyla-[3-methoxybenzoyl)succinate, b.p. l62.9 C. (04-05mm.).-Infraredanalysis of the product shows characteristic peaks at 5.75and 5.90 microns.

Elemental analysis gives the following results: Calcd. for C I-1 C,59.99; H, 5.75. Found: C, 59.91; H, 5.79.

In similar manner, the corresponding diethyl, dipropyl and di-t-butylesters are prepared.

3 8 EXAMPLE XLIII Ethyl 3-carbo-t-butoxy-3- S-methoxybenzoyl) propionateA mixture of 15.8 g. of the product of Example XLI 10.5 g. of ethylbromoacetate and 3.02 g. of sodium hydride in 130 ml. ofdimethylformamide is treatedas in Method A of Example XLII to'obtainthis product as a yellow oil. 'Infrared analysis of the product showscharacteristic peaks at 5.75 and 5.90 The product is used withoutdistillation in the procedure of Example X-LVI to produce ethyl3-.[carbo-t-butoxy-3a(2-cyanoethyl) -3- (3-methoxybenzoyl) propionate.

EXAMPLE XLIV Diethyl 3-carbethoxy-3-(3-methoxybenzoyl) adipate To amixture of 102 g. of diethyl u-(3-methoxybenzoyl 'succinate in 250ml. ofdioxane and 10 ml. of a 35% solution of benzyltrimethylammoniumhydroxide in methanol maintained at 50 C. is added 167- g. of ethylacrylate in one portion with stirring. Heating and stirring arecontinued for 30 minutes, after which 10 ml. of glacial acetic acid isadded. The mixture is evaporated under reduced pressure to a dark oilwhich is distilled in vacuo to yield 80.5 g. of the diethyl esterproduct, b.p. 197 C. (0.1-0.2 mm.), n =1.5043. Infrared analysis showscharacteristic peaks at 5.76 and 5.92 1.

Elemental analysis gives the following results: Calcd. for C H O C,61.75; H, 6.91. Found: C, 61.64; H, 6.90.

Dimethyl and dipropyl B-carbomethoxy-3-(3-methoxybenzoyl)adipate areprepared in similar fashion.

EXAMPLE XLV Diethyl 3-carbo-t-butoxy-3- 3-methoxybenzoyl') adipate Theproduct of Example XLIII a yellow oil, is dissolved in ml. of t-butanolcontaining 0.75 g. of potassium t-butoxide and 19 g. of ethyl acrylate.The mixture is refluxed for 1.3 hours and then concentrated underreduced pressure to obtain the adipate ester product, a yellow viscousoil, which is used without distilaltion in the procedure of Method B ofExample XLVII.

EXAMPLE XLVI u- 3-Methoxybenzoyl oc- Z-cyanoethyl) succinic acid diethylester This compound is prepared according to the procedure of ExampleXLIV using acrylonitrile or fi-bromopropionitrile in lieu of ethylacrylate. The product is vacuum distilled at 212-218 C. (0.45 mm. Hg).This product is hydrolyzed and decarboxylated to3-(3methoxybenzoyl)adipic acid by refluxing in aqueous acetic acidcontaining sulfuric acid by the procedure of Method A of Example XLVII.Corresponding esters are prepared in the usual manner.

EXAMPLE XLVII Diethyl 3-(3-methox'ybenzoyl)adipate Method A: A mixtureof 25 g. of diethyl-3-carbethoxy- 3-(3-methoxybenzoyl)adipate in 30 ml.of acetic acid, 10 ml. of concentrated sulfuric acid and 10 ml. of wateris refluxed for 36 hours. The mixture is then poured into excess waterand extracted with chloroform, the extract dried and evaporated underreduced pressure to an oil. The oil is dissolved in a mixture of 50 ml.of ethanol, 1 liter of ethylene dichloride and 6 ml. of concentratedsulfuric acid and refluxed for 12 hours. The mixture is then poured intowater. The ethylene chloride layer is separated, dried and evaporated invacuo to an oil which is distilled to obtain 5.5 g. of product, b.p.169- 172 C. (0.05 mm.), n =l.5092.

Elemental analysis gives the following results: Calcd. for C H O C,64.27; H, 7.19. Found: C, 64.09; H, 7.19.

In similar fashion, the dimethyl and dipropyl esters are prepared.

Method B: The product of Example XLV a yellow viscous oil, is refluxedin 120 ml. of dry xylene containing 3.0 g. of p-toluenesulfonic acid andcooled and extracted with water. The xylene solution, after drying, isconcentrated under reduced pressure and the residual oil vacuumdistilled to obtain 6.8 g. of product.

There is also obtained 5.86 g. of the enol lactone:

CH: O

a red oil, which on infrared absorption analysis showed a maximum at5.58;.

As is recognized by those in the art, the product of this example is aracemic compound, DL-3-(3-methoxybenzoyl)adipic acid diethyl esterwhich, as the free acid, lends itself to resolution into the opticalactive forms by salt formation with optically active bases such asbrucine, cinchonine, cinchonidine, morphine and the like to formdiastereoisomers. Such procedures are well known to those skilled in theart. Of course, the optically active forms (antipodes) after separation,may be converted one to the other, as desired, by racemization andresolu tion. The present compound, in one of its optically active forms,is racemized by treating it with a strong base in solvent, e.g. sodiumhydride, hydroxide or alkoxide in a lower alkanol. After racemization,the desired optical form may be resolved and the procedure repeated toproduce more of the desired optical form from its antipode.

EXAMPLE XLVIII Employing the procedure of 'Example XL the followingcompounds are prepared from corresponding starting compounds, Thosecompounds having an active hydrogen require the use of an additionalmole of sodium hydride.

methylbenzoylacetate ethyl (2-ethyl-5-hydroxybenzoyl)acetate methyl2-(S-methoxybenzoyl)propionate methyl 2-(S-methoxybenzoyl)butanoatemethyl 2- S-methoxybenzoyl) pentanoate methyl(2-chloro-5-methoxybenzoyl)acetate methyl(2-dimethylamino-S-methoxybenzoyl)acetate methyl(2-amino-5-methoxybenzoyl)acetate methyl(2-acetamido-5-methoxybenzoyl)acetate ethyl (-hydroxybenzoyl)acetateethyl (Z-methoxybenzoyl)acetate ethyl (3-hydroxybenzoyl) acetate ethyl(2-methyl-5-hydroxybenzoyl)acetate ethyl(2,3-dimethyl-5-hydroxybenzoyl)acetate ethyl(3-isopropyl-S-hydroxybenzoyl)acetate ethyl(2,3-diethyl-S-hydroxybenzoyl)acetate ethyl (S-benzyloxybenzoyl)acetateethyl (3-methyl-5-hydroxybenzoyl)acetate ethyl(3-dimethylamino-S-hydroxybenzoyl)acetate methyl(2,3-dimethylbenzoyl)acetate ethyl (3,5-dimethoxybenzoyl)acetate ethyl(2,3-diethyl-5-ethoxybenzoyl)acetate ethyl (3-isopropyl-5-ethoxybenzoylacetate methyl (Z-methylamino-S-methoxybenzoyl)acetate methyl(3-ethyl-5-methoxybenzoyl acetate ethyl (2-methoxy-S-benzyloxybenzoyl)acetate ethyl (2-propyl-5-propoxybenzoyl acetate ethyl(3-trifluoromethyl-S-methoxybenzoyl)acetate ethyl(3-acetoxy-S-methoxybenzoyl) acetate propyl (3-propoxybenzoyl)acetatebenzyl (2-chloro-5-methoxybenzoyl)acetate ethyl (3-benzyloxybenzoylacetate ethyl (3-amino-S-benzyloxybenzoyl)acetate ethyl(3-propyl-5-methoxybenzoyl)acetate ethyl(2-isopropyl-3-ethyl-5-methoxybenzoyl)acetate 40 benzoyl 2-(Z-methoxy-5-ethoxybenzoyl) acetate benzyl(2-chloro-3-methyl-5-methoxybenzoyl)acetate ethyl(2-ch1oro-3-dimethylamino-5-methoxybenzoyl) acetate methyl(2-chloro-4-acetamidobenzoyl)acetate methyl(2-chloro-3-acetamido-S-methoxybenzoyl)acetate methyl(2,3-ditrifiuoromethyl-S-methoxybenzoyl)acetate methyl(2-methyl-3-propionyloxybenzoyl)acetate ethyl(2-trifluoromethyl-3,S-dibutoxybenzoyl)acetate ethyl(2-trifiuoromethyl-3-ethylamino-5-methoxybenzoyl) acetate ethyl(3-butyrylamidobenzoyl) acetate ethyl(2-chloro-3-acetoxy-5-ethoxybenzoyl)acetate ethyl(2-chloro-3,S-dihydroxybenzoyl)acetate ethyl(3-acetamido-S-hydroxybenzoyl)acetate ethyl(3-trifiuoromethyl-5-hydroxybenzoyl) acetate EXAMPLE XLIX The followingcarbalkoxybenzoyl propionates are prepared from corresponding benzoylacetates by reaction with u-haloacetic acid esters according to theprocedure of Method A of Example XLII, as well as by the procedure ofMethod B, Example XLII.

ethyl 3-carbomethoxy-3-benzoylpropionate methyl3-carbethoxy-3-(2-ethyl-5-methoxybenzoyl) propionate methyl3-carbomethoxy-3-(3-methoxybenzoyl)butanoate* methyl3-carbomethoxy-3-(3-methoxybenzoyl) pentanoate* methyl3-carbomethoxy-3-(3-methoxybenzoyl)hexanoate* methyl3-carbomethoxy-3-(2-chloro-5-methoxybenzoyl) propionate methyl3-carbomethoxy-3-(2-dimethylamino-S-methoxybenzoyl)propionate benzyl3-carbomethoxy-3-(Z-acetamido-S-methoxybenzoyl) propionate benzyl3-carbomethoxy-3-(Z-acetamido-S-methoxybenzoyl)propionate ethyl3-carbethoxy-3- 3-methoxybenzoyl propionate ethyl3-carbethoxy-3-(2,3-diethyl-S-methoxybenzoyl) propionate ethyl3-carbethoxy-3-(3-isopropyl-5-methoxybenzoyl) propionate ethyl3-carbethoxy-3-(2-methyl-5-ethoxybenzoyl) propionate ethyl3-carbethoxy-3-(3-dimethylamino-S-propoxybenzoyl)propionate methyl3-carbomethoxy-3-(2,3-dimethylbenzoyl) propionate ethyl3-carbethoxy-3-(3-methoxybenzoyl)propionate ethyl3-carbethoxy-3-(2-methyl-5-methoxybenzoyl) propionate ethyl3-carbethoxy-3-(4-methyl-S-methoxybenzoyl) propionate ethyl3-carbethoxy-3-(2,3-dimethyl-S-methoxybenzoyl) propionate ethyl3-carbethoxy-3- 3-benzyloxybenzoyl propionate ethyl 3-carbethoxy-3-3,S-dimethoxybenzoyl)propionate ethyl3-carbethoxy-3-(2,3-diethyl-5-ethoxybenzoyl) propionate ethyl3-carbethoxy-3-(3-isopropyl-5-ethoxybenzoyl) propionate methyl3-carbomethoxy-3-(2-methylamino-5-methoxybenzoyl)propionate methyl3-carbomethoxy-3(3-ethyl-5-methoxybenzoyl) propionate ethyl3-carbethoxy-3-(2-methoxy-S-benzyloxybenzoyl) propionate ethyl3-carbethoxy-3-(2-propyl-5-propoxybenzoyl) propionate *The higherbenzoyl alkanoates, e.g. butanoate, pentanoate and hexanoate, areprepared from the next lower homolog by the procedure of Method A,Example XLII.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULAE